DHCR24 in cholesterol metabolism and diseases of the nervous system

Abstract

DHCR24 (3β-hydroxysterol 24-reductase) is a critical enzyme that plays an essential role in the cholesterol biosynthesis pathway, which catalyzes the reduction of the sterol intermediate C-24 double bond. DHCR24 is also involved in cell growth, senescence, and cellular responses to carcinogenesis and oxidative stress. DHCR24 is extensively studied, particularly in neurodegenerative diseases like Alzheimer’s disease. It is thought to have neuroprotective effects such as resistance to amyloid β-peptide (Aβ) toxicity and oxidative stress. Nevertheless, there is a notable absence of systematic reviews integrating these two domains. Meanwhile, disordered lipid metabolism has been increasingly recognized in recent years as a critical contributor to the pathogenesis and progression of ischemic stroke and other neurological disorders, and DHCR24, as a key mediator in this process, has become an indispensable research target. Therefore, this review aims to comprehensively summarize the role of DHCR24, from its central function in cholesterol biosynthesis to its implications in neurological disorders.

Introduction

DHCR24, also known as seladin-1 (selective Alzheimer’s disease indicator-1), was initially identified based on its downregulation in the temporal cortex of Alzheimer’s disease (AD) patients, from which it transiently acquired this nomenclature [1]. However, subsequent research has revealed that this nomenclature was premature, largely due to limitations in early studies that included restricted sample sizes and methodological constraints, which undermined its classification as a definitive AD susceptibility gene [2]. It is now recognized that DHCR24 is a multifunctional protein, not only catalyzing the reduction of desmosterol to cholesterol in the cholesterol biosynthesis pathway but also serving as a regulator of steroidogenesis and a sensor of cellular stress with protective functions [3]. In light of these expanded roles, the systematic name DHCR24 has superseded the earlier designation seladin-1 to better reflect its diverse biological significance.

DHCR24 is widely and abundantly expressed across multiple human organs, including the brain, heart, liver, kidneys, lungs, thyroid, ovaries, testes, and prostate [1, 4, 5]. Within the mammalian central nervous system (CNS), it is ubiquitously present in regions such as the cerebral cortex, caudate nucleus, subthalamic nucleus, hippocampus, and cerebellum, with particularly high levels observed in the medulla oblongata and spinal cord [1] (Fig. 1). In peripheral tissues, DHCR24 shows prominent expression in the zona fasciculata and zona reticularis of the adrenal cortex in humans. Interestingly, adult rats exhibit a divergent expression profile, with strong localization in the zona fasciculata, minimal presence in the zona glomerulosa, and markedly weaker expression in the zona reticularis [3, 6].

Fig. 1.

Distribution of DHCR24. The illustration demonstrates the relatively high abundance and distribution of DHCR24 across various human organ systems. The left panel presents the comprehensive distribution of DHCR24 throughout human organ systems, whereas the right panel displays its specific distribution in the human brain. Darker color intensity denotes higher expression levels in the corresponding anatomical regions. Figure created with BioRender

As an essential reductase in cholesterol biosynthesis, DHCR24’s central role in lipid metabolism is well established. Nevertheless, its neuroprotective mechanisms within the nervous system remain incompletely understood. While several reviews have addressed the role of DHCR24 in AD, no comprehensive review has yet systematically elucidated its mechanistic contributions and pathological relationships across the spectrum of neurological disorders [2, 7, 8]. Recent advances in multi-omics research have provided powerful tools for elucidating molecular and cellular mechanisms underlying neural injury and regeneration [9]. Building upon these emerging systems-level frameworks, this review synthesizes current knowledge on the regulatory functions of DHCR24 in lipid metabolism and CNS physiology, while critically evaluating emerging evidence regarding its potential involvement in the pathogenesis of neurological disorders.

Search strategy

This manuscript presents a comprehensive review based on systematic literature searches conducted across three authoritative databases: PubMed Central, Web of Science Core Collection, and China National Knowledge Infrastructure. No date restrictions were applied to the search, and all eligible publications up to the date of the final literature search were considered for inclusion.

The exact search terms and their standard Boolean logical combinations (using AND/OR operators) were applied for retrieval. The core search terms are categorized as follows: Target-related terms: DHCR24, 3β-hydroxysterol-Δ24-reductase, seladin-1. Function-related terms: cholesterol biosynthesis, cholesterol metabolism, transcription. Disease-related terms: central nervous system diseases, CNS disorders, neurological disorders, neurological diseases, Huntington’s disease, Parkinson’s disease, synucleinopathies, frontotemporal dementia, glioblastoma, primary brain tumors.

We defined clear inclusion and exclusion criteria for literature screening: eligible publications were peer-reviewed original research articles and comprehensive review articles written in English or Chinese that focused on the association between DHCR24, CNS diseases and cholesterol metabolism, while duplicate records, non-English/Chinese literature, and studies irrelevant to the core theme of this manuscript were excluded. Initial retrieval across the three databases yielded a total of 837 records. Duplicate records and irrelevant literature were excluded through preliminary screening via title and abstract review. Ultimately, a total of 165 eligible publications were included and cited in this manuscript.

The structure and function of DHCR24

DHCR24, also known as 3β-hydroxysterol-Δ24-reductase, functions as a key enzyme in cholesterol biosynthesis and is encoded by a gene located on chromosome 1p31.1–p33. The gene spans approximately 46.4 kb of genomic deoxyribonucleic acid (DNA) and consists of nine exons and eight introns​​ [10]. Its transcript includes an open reading frame of 1,548 nucleotides, encoding a protein of 516 amino acids with a predicted molecular weight of 60.1 kDa. The encoded protein contains a highly conserved flavin adenine dinucleotide (FAD)-binding domain, which exhibits remarkable evolutionary conservation across DHCR24 orthologs from animal to plant species, indicating its membership in the FAD-dependent oxidoreductase family. Notably, DHCR24 shares significant sequence homology with plant sterol oxidoreductases such as DWARF1/DIMINUTO, underscoring its evolutionary conservation and functional relevance in sterol metabolism ​​ [1].

DHCR24 is a ubiquitously expressed enzyme that plays multifaceted roles in cellular homeostasis and protection across various biological systems. Since its initial identification in 2000, accumulating experimental evidence has established its significant neuroprotective functions. These include the amelioration of Aβ-induced toxicity, attenuation of oxidative stress, and inhibition of apoptotic pathways through suppression of caspase-3 activation [1]. Further extending its cytoprotective profile, DHCR24 also confers resistance to endoplasmic reticulum stress-induced apoptosis by effectively scavenging excess reactive oxygen species (ROS), thereby maintaining redox homeostasis under stress conditions​ [11]. Notably, DHCR24 has emerged as a potential mediator in hormone-dependent neuroprotective mechanisms. It is implicated in estrogen receptor-mediated neuroprotection, as supported by a clear dose-dependent correlation between DHCR24 messenger ribonucleic acid (mRNA) expression levels and the neuroprotective efficacy of selective estrogen receptor modulators (SERMs), including raloxifene and tamoxifen [12]. Analogously, DHCR24 serves as a crucial intermediary in thyroid hormone-mediated neuroprotection, where it helps safeguard neural precursor cells from developmental apoptosis, highlighting its importance in CNS development and maintenance [13]. The regulation of DHCR24 expression under metabolic stress conditions further underscores its pathophysiological relevance. In fetal neuroepithelial cells (FNC) cell models, a neuronal lineage established through cloning and long-term in vitro propagation from human fetal olfactory neuroepithelium and exhibiting neuroendocrine features, insulin-like growth factor 1 (IGF-1) robustly upregulates DHCR24 expression, whereas both intermittent high glucose exposure (20/10 mM) and sustained hyperglycemia (20 mM) markedly downregulate its mRNA levels [14]. These findings implicate DHCR24 in IGF-1-regulated neuropathological processes, particularly in the context of diabetic neuropathy. Beyond its established roles in neuroprotection and metabolic regulation, emerging research indicates that DHCR24 upregulation contributes to the anti-inflammatory effects of reconstituted high-density lipoprotein (rHDL) and its primary protein component, apolipoprotein A-I (ApoA-I) [15, 16]. This novel function suggests a broader therapeutic potential for DHCR24 in inflammatory-related disorders.

Transcriptional regulation of DHCR24

The expression and function of the DHCR24 gene are governed by a sophisticated multi-level regulatory architecture that integrates metabolic, hormonal, and epigenetic signals [17–20]. Extensive genomic analyses have delineated a complex promoter structure, wherein the distal region harbors binding sites for nuclear hormone receptors including the estrogen receptor and androgen receptor, a direct repeat 4 (DR4)-type sequence for constitutive androstane receptor/retinoid X receptor (CAR/RXR) and pregnane X receptor/retinoid X receptor (PXR/RXR) heterodimers, while the second intron contains a functional liver X receptor (LXR) response element. The proximal promoter itself is a single, cytosine-phosphate-guanine (CpG)-rich, and thymine-adenine-thymine-adenine (TATA)-less sequence, characteristic of a broad-class promoter with multiple transcription start sites [21]. This region is subject to dynamic epigenetic regulation, where DNA methylation of the CpG island potently represses transcription, and histone acetylation, particularly within an enhancer region (–1203/–665), activates it [21]. This epigenetic layer explains the cell-type-specific expression of DHCR24 and its downregulation in pathological contexts like AD, suggesting histone deacetylase (HDAC) inhibitors as potential therapeutic agents to restore its expression. Furthermore, central to the metabolic regulation of DHCR24 is its direct control by cholesterol availability via the sterol regulatory element-binding protein (SREBP) pathway. The proximal promoter contains a canonical sterol regulatory element (SRE) at position − 98/–90, which is essential for both basal and cholesterol-responsive transcription [17]. Upon cellular cholesterol depletion, SREBPs are processed and bind to this SRE, thereby activating DHCR24 transcription. This response is augmented by the presence of binding sites for co-activators such as nuclear factor-Y (NF-Y) and specificity protein 1 (Sp1) in the immediate vicinity. Intriguingly, although androgens synergize with SREBP activation to elevate DHCR24 mRNA levels, this effect is not mediated by the proximal promoter, indicating the functional necessity of the distal androgen response element (ARE) and underscoring the complexity of hormonal and metabolic crosstalk [17, 21].

Beyond this intricate transcriptional and epigenetic control, a crucial layer of post-transcriptional regulation has been identified. The microRNA miR-7 directly targets the 3’ untranslated region (3’UTR) of DHCR24 mRNA, leading to its translational repression and degradation [20]. This mechanism was validated both in vitro and in vivo, as intracranial infusion of miR-7 via an adeno-associated viral vector significantly reduced DHCR24 expression in the mouse brain. Intriguingly, this post-transcriptional regulation is integrated into a metabolic feedback loop: cellular cholesterol depletion activates SREBP2, which not only transactivates the DHCR24 gene but also upregulates the transcription of miR-7, which is hosted within the intron of the heterogeneous nuclear ribonucleoprotein K (HNRNPK) gene, thereby establishing a fine-tuned, homeostatic circuit to prevent cholesterol over-synthesis.

The functional outcome of this intricate transcriptional regulation is the synthesis of the DHCR24 enzyme, a pivotal protein in cholesterol metabolism that localizes to the endoplasmic reticulum. Its membrane topology is precisely defined, featuring an N-terminal domain oriented toward the endoplasmic reticulum lumen and a C-terminal domain, which contains the catalytic FAD-binding site, facing the cytoplasm [22] (Fig. 2). This N-terminal luminal/C-terminal cytoplasmic orientation is critical for its enzymatic function in cholesterol biosynthesis, as it positions the catalytic domain to access sterol substrates present in the cytoplasmic leaflet of the endoplasmic reticulum membrane. The functional significance of this catalytic positioning is underscored by the consequences of its inhibition; for instance, miR-7-mediated suppression of DHCR24 leads to a marked accumulation of its substrate, desmosterol, and a concomitant reduction in de novo cholesterol synthesis in neuronal cells [20]. Furthermore, this topological arrangement situates the C-terminal domain as a sensor and effector in the cytoplasmic compartment, facilitating its additional role as a scavenger of ROS. Notably, this ROS scavenging activity is maintained even in a transmembrane domain-deleted mutant that localizes to the cytoplasm, demonstrating that the anti-apoptotic function can be spatially uncoupled from its endoplasmic reticulum-localized cholesterol synthesis role. However, the in vivo mechanisms underlying this functional uncoupling remain to be elucidated.

Fig. 2.

Location of DHCR24. Subcellular localization of DHCR24 at the endoplasmic reticulum (ER). The N-terminus of DHCR24 is oriented towards the ER lumen, while its C-terminus and flavin adenine dinucleotide (FAD)-binding domain face the cytosol. Figure created with BioRender

Beyond endogenous regulation, DHCR24 is a key target for pharmacological inhibition. Recent studies employing molecular dynamics simulations have revealed that the small molecule U18666A acts as an allosteric inhibitor. U18666A does not compete with the substrate desmosterol for the active site but instead binds to a hydrophobic pocket near the FAD cofactor [23]. This binding induces conformational changes in DHCR24, including alterations in secondary structure and the formation of new hydrogen bonds with key residues like Lys292 and Lys367. These changes paradoxically increase the binding affinity of both the FAD cofactor and the desmosterol substrate but ultimately suppress the catalytic conversion to cholesterol, characteristic of a non-competitive, allosteric mechanism [23]. Leveraging this specific mechanism, U18666A has been widely adopted as a selective tool to inhibit DHCR24 activity, proving invaluable in establishing cellular and animal models of cholesterol dysregulation, such as those mimicking aspects of Niemann-Pick type C disease and Alzheimer’s pathology.

In conclusion, the transcriptional output of DHCR24 is determined by the concerted integration of signals from its distal and proximal regulatory elements. The SREBP pathway provides a direct link to the cellular sterol status, while nuclear hormone receptors and epigenetic modifiers fine-tune its expression. The resulting protein product adopts a defined endoplasmic reticulum topology that supports its dual enzymatic and protective functions, which can be selectively disrupted by allosteric inhibitors like U18666A, highlighting DHCR24 as a critical node at the intersection of cholesterol metabolism, oxidative stress response, and therapeutic intervention. Although contemporary research has considerably advanced our comprehension of DHCR24’s transcriptional regulation, substantial knowledge gaps persist concerning its complete regulatory circuitry. The anticipation remains that future investigations will reveal novel transcriptional pathways associated with this gene, thereby potentially facilitating the development of targeted therapeutic interventions for pathologies in which DHCR24 dysfunction plays a contributing role.

DHCR24 and cholesterol biosynthesis

Cholesterol biosynthesis is a multi-step process comprising two major phases: the pre-mevalonate pathway and the post-squalene pathway, the latter also referred to as distal cholesterol biosynthesis. The distal biosynthetic process bifurcates into two interconnected, yet functionally divergent branches that operate in a mutually compensatory manner: the classical Bloch pathway and the Kandutsch-Russell (KR) pathway (Fig. 3). This complex metabolic network involves the coordinated action of over twenty enzymatic components. Notably, DHCR24 holds a strategic position in this biosynthetic cascade as a pivotal enzyme with dual regulatory significance. It not only function as a critical metabolic node linking the Bloch and KR pathways but also acts as the terminal enzyme in the Bloch pathway, where it catalyzes the reduction of the C-24 double bond in sterol intermediates. This reaction represents the ultimate step in cholesterol biosynthesis, with emerging evidence suggesting that approximately 90% of DHCR24’s enzymatic activity within the entire cholesterol synthesis pathway is specifically dedicated to this final conversion step [24, 25]. Thus, through its position and functional specialization, DHCR24 operates as a central regulatory node whose modulation exerts direct control over cholesterol production.

Fig. 3.

A simplified schematic of the biosynthesis of cholesterol from scratch. This synthesis includes the Bloch pathway and the Kandutsch-Russell pathway, ultimately resulting in the production of cholesterol. The black dashed arrows and ellipses indicate omitted intermediate parts that are not shown. Figure created with BioRender

Beyond its enzymatic role, DHCR24 exhibits complex subcellular localization and functional interplay with other sterol biosynthesis enzymes. Immunofluorescence and confocal imaging studies have revealed that DHCR24 co-localizes with 7-dehydrocholesterol reductase (DHCR7) and emopamil binding protein (EBP) in the endoplasmic reticulum and nuclear envelope, yet their distribution patterns are not entirely overlapping, suggesting that these enzymes may not always operate within a single functional complex [26]. Importantly, in vivo evidence from DHCR7 knockout mice demonstrates a compensatory upregulation of DHCR24 protein expression in the brain, indicating a physiological adaptation that potentially shifts cholesterol synthesis toward the Bloch pathway when the KR pathway is impaired [26]. This compensatory mechanism highlights the metabolic plasticity of the cholesterol biosynthesis network and underscores DHCR24’s central role in maintaining sterol homeostasis under genetic or pathological stress.

In 2014, Luu et al. experimentally demonstrated that phosphorylated DHCR24 not only reduces cholesterol biosynthesis but also increases desmosterol accumulation, thereby exerting dual modulation of sterol homeostasis; however, the precise molecular mechanisms underlying these effects remain to be fully elucidated [27]. Complementing these findings, Li and colleagues employed an in vitro model of human granulosa-lutein (GL) cells to establish that transforming growth factor-β (TGF-β) suppresses de novo cholesterol biosynthesis through downregulation of DHCR24 expression via the glycogen synthase kinase 3β/Enhancer of Zeste Homologue 2/Histone H3 lysine 27 trimethylation (GSK3β/ EZH2/H3K27me3) signaling axis [28]. In a parallel discovery that further underscores the therapeutic relevance of DHCR24 inhibition, the work by Simonen et al. combining clinical specimen analysis with in vitro experimentation to reveal that amiodarone directly inhibits DHCR24 enzymatic activity, resulting in pathological accumulation of desmosterol [29]. However, these studies were only limited to the interrelationship between DHCR24 and cholesterol synthesis, and did not propose ideas or treatment protocols that could be immediately applied to the clinic. Building upon previous foundational research, Wang et al. conducted a pioneering study in 2023 that proposed inhibiting DHCR24 to block cholesterol synthesis as a novel lipid-lowering strategy, representing the first such approach globally [30]. Through an integrated approach combining virtual drug screening, molecular dynamics simulations, and extensive in vivo and in vitro validations, the researchers conclusively demonstrated that Irbesartan, a commercially available antihypertensive agent, potently inhibits DHCR24 enzymatic activity. Notably, however, the precise molecular mechanism underlying this inhibition remains to be fully elucidated, representing a critical direction for future investigation. Beyond its specific findings, this study offers a broader insight into drug discovery: the development of novel therapeutics does not necessarily require de novo synthesis of previously unknown compounds. The repurposing and mechanistic rediscovery of existing drugs, which is effectively exemplified by Irbesartan in this context, represents a promising and resource-efficient direction for future pharmacological research, particularly in metabolic and neurodegenerative disorders.

In recent years, more and more research focuses on metabolome reprogramming and therapy, so a German research team investigated the relationship between DHCR24 and immunoinflammation by acting on DHCR24 with a DHCR24 inhibitor probe (SH42), and ultimately came to the conclusion of discovering that interfering with lipid metabolism at a certain site can trigger endogenous polyunsaturated fatty acid (PUFA) biosynthesis and downstream pro-lipolytic lipid production, and this can also lead to some important functional and phenotypic changes [31]. Earlier, in 2006, Crameri et al. found through in vivo and in vitro experiments that DHCR24 deficiency leads to a reduction in membrane cholesterol levels in the mouse brain, which leads to alterations in DRM, which in turn contributes to a reduction in membrane binding of fibrinogen and fibrinolytic activation, resulting in in vivo amyloid precursor protein (APP)-β cleavage and increased Aβ production in vivo [32]. This can help us to explain AD from a pathological point of view. Subsequently, DAIMIEL et al. demonstrated in 2012 that the presence of an SRE sequence in the DHCR24 promoter and noted that it was highly similar to the SRE sequence in the low-density lipoprotein receptor (LDLR) promoter, and suggested that this site mediates SREBP binding and thus responds to cholesterol availability [17]. In 2014, Zerenturk et al. further advanced the structural understanding of DHCR24 [33], proposing that DHCR24 binding to endoplasmic reticulum membranes is not dependent on the N-terminus of transmembrane domain (TMD), but rather the membrane-bound region beyond the hydrophobic N-terminus, a view that is exactly the opposite of Lu [22]. They suggested that the binding of DHCR24 to the core hydrophobic region of the lipid bilayer of the endoplasmic reticulum results from the action of multiple hydrophobic structural domains. More recently, in 2021, Sliz et al. found a genome-wide significant association of rs588709 in the vicinity of DHCR24 by studying visceral adipose, circulating phospholipid phosphatidylcholines (PCs), and cerebral white matter from 931 adolescents, which were associated with adolescent brain health development and peripheral metabolism [34]. Collectively, these findings establish DHCR24 as a pivotal regulatory node in cholesterol biosynthesis and beyond, whose expression and activity can be therapeutically targeted to modulate metabolic flux with broad physiological implications.

Cholesterol and neurological disorders

Cholesterol is universally recognized as a fundamental structural constituent of eukaryotic cell membranes, where it serves to modulate membrane fluidity and permeability [35]. Moreover, beyond its structural role, cholesterol functions as the indispensable biosynthetic precursor for all steroid hormones and bile acids. Furthermore, it participates critically in essential cellular processes including membrane trafficking and transmembrane signal transduction [35]. Notably, it is well-established that cholesterol constitutes an essential component of the central nervous system, with approximately 25% of total body unesterified cholesterol residing within the brain [36, 37]. Since the blood-brain barrier (BBB) prevents peripheral cholesterol from entering the brain, this pool relies heavily on continuous de novo synthesis to meet metabolic demands.

Intriguingly, even under such isolation, elevated cerebral cholesterol levels have been observed in mice fed high-fat diets, suggesting a potential link between peripheral lipid metabolic disturbances and neurological function [38]. A growing body of research now indicates that peripheral dyslipidemia and oxidative stress can impair BBB integrity and promote neuroinflammation, thereby contributing to cognitive decline [39, 40]. A new finding builds upon prior research demonstrating that dysregulated peripheral lipid metabolism can compromise BBB integrity and contribute to cognitive impairment. Notably, these observations collectively underscore the intricate interplay between systemic metabolic homeostasis and neurological health [41, 42].

In a study utilizing a rat model of prenatal malnutrition, researchers employed microarray analysis and weighted gene co-expression network analysis (WGCNA) to examine transcriptomic changes in the hippocampi and prefrontal cortices of offspring. Their analysis identified three significant modules in the hippocampus that were enriched for synaptic development and neuronal functions, leading to the identification of fifteen hub genes. Among these, DHCR24 expression was significantly upregulated in malnourished offspring, suggesting that cholesterol biosynthesis may be implicated in the observed neurodevelopmental impairments [43], which is consistent with the results of a prior genomic imprinting study conducted on the placenta [44].

A growing body of compelling experimental evidence underscores the indispensable role of cholesterol in CNS homeostasis, wherein even minor perturbations in its biosynthetic pathway can precipitate profound structural and functional aberrations. Cholesterol synthesis is a tightly regulated multi-enzymatic process. Consequently, the deficiency or dysfunction of any single enzyme, particularly those controlling rate-limiting steps, can disrupt neurodevelopmental processes, synaptic plasticity, and axonal guidance. Such disruptions may ultimately contribute to the pathogenesis of neurodegenerative and neurodevelopmental disorders. Notably, experimental studies have further revealed that while peripheral hyperlipidemia induces neurological damage, this pathological state is concomitantly associated with reduced DHCR24 expression. These findings collectively highlight the critical role of cholesterol metabolism in neural integrity and suggest DHCR24 as a potential mediator linking systemic lipid dysregulation with CNS dysfunction [38].

Furthermore, loss-of-function mutations in DHCR24 impair the final step of cholesterol biosynthesis, leading to the pathological accumulation of desmosterol, a metabolic precursor that typically constitutes < 1% of total sterols in peripheral tissues. Strikingly, in the developing mammalian brain, where cholesterol demand is exceptionally high, desmosterol levels can escalate to 30% of total sterol content under conditions of DHCR24 deficiency [45–47]. This aberrant accumulation culminates in a severe neurodevelopmental disorder globally known as desmosterolosis [10]. Accordingly, in the subsequent sections, we systematically synthesize and critically evaluate recent discoveries and advancements in the understanding of this disorder, with the aim of providing a comprehensive perspective on emerging mechanistic insights and therapeutic implications.

Desmosterolosis (Fig. 4) is an autosomal recessive genetic disorder of cholesterol biosynthesis [10], first reported by FitzPatrick et al. in 1998 [48]. Their initial case described an infant with macrocephaly, an underdeveloped nasal bridge, cleft palate, and osteoporosis. Gas chromatography-mass spectrometry analysis revealed an abnormal increase in desmosterol levels; unfortunately, the infant died shortly after birth. A subsequent case reported by Andersson et al. in 2002 revealed a surviving patient with a distinct set of clinical features, including talipes equinovarus, persistent arterial ductus, downward slanting palpebral fissures, and agenesis of the corpus callosum [49]. Due to the variable clinical presentations observed in the first two reported cases of Desmosterolosis, it is not possible to generalize the phenotype of this disease. It was not until nine years later, in 2011, that this disease was reported again in the literature. Zolotushko et al. summarized four cases of Desmosterolosis in Israeli Bedouin individuals, all of whom presented with growth retardation, psychomotor delay, microcephaly, retrognathia, and various degrees of hand contractures [50]. They identified DHCR24 mutations as missense mutations affecting a highly conserved amino acid in the FAD-binding domain of the protein. In the same year, Schaaf et al. reported one case of Desmosterolosis and identified the causative mutations c.281G > A (p.R94H) and c.1438G > A (p.E480K), inherited from the parents [51]. They measured the lipid profile of the infant at 3 days of age and found slightly elevated cholesterol levels compared to normal infants of the same age, along with significantly increased desmosterol levels. This led them to speculate that the residual activity of DHCR24 prevented a decrease in cholesterol levels. Considering the molecular mechanism of Desmosterolosis involving FAD and nicotinamide adenine dinucleotide phosphate (reduced form, NADPH), Schaaf et al. attempted to increase the residual activity of DHCR24 by modulating the levels of FAD and NADPH. However, the insufficiency of clinical evidence, particularly the limited number of documented cases, hinders a robust validation and definitive establishment of the generalizability and efficacy of this therapeutic strategy.

Fig. 4.

Timeline of reported cases of desmosterolosis: a global rare disease. Temporal distribution of reported desmosterolosis cases from first identification to present, showing associated patient survival data and DHCR24 mutation profiles. Figure created with BioRender

Following this, Dias et al. conducted a longitudinal observation of a pair of monozygotic twins from birth and found that the phenotypic and genotypic manifestations of the disorder were inconsistent [52]. However, the consistent presence of developmental delay, central nervous system malformations, spasticity (with or without distal joint contractures), and short stature provided sufficient diagnostic criteria for screening cholesterol synthesis disorders. Four years later, Mersedeh et al. reported a case of a 20-month-old male infant with consanguineous parents presenting multiple congenital anomalies, including agenesis of the corpus callosum, facial dysmorphism, cleft palate, sternal deformity, and a short, broad neck [53]. The authors identified a homozygous likely pathogenic variant (p.Glu191Lys) in the DHCR24 gene as the underlying genetic cause of the disorder. With the rapid advancement of genetic diagnostics, Hill et al. diagnosed the eleventh reported case of Desmosterolosis via prenatal whole-exome sequencing in 2022 [54]. They identified a potentially pathogenic homozygous variant c.571G > A p.(Glu191Lys) in the DHCR24 gene (LGR_1272t1) and also reported symptoms of renal dysplasia and coarctation of the aorta for the first time. Most recently, in 2024, Dario et al. demonstrated that the homozygous missense variant NM_014762.4:c.506T > C, NP_055577.1:p.M169T in DHCR24 likewise leads to the development of desmosterolosis [55]. This finding provides a novel diagnostic site and enhances the genotypic profiling value for the molecular diagnosis of this disorder.

In summary, although the currently documented cases of desmosterolosis exhibit considerable phenotypic heterogeneity, a constellation of overlapping clinical features emerges as pathognomonic hallmarks that may be collectively delineated as: intellectual disability, agenesis of the corpus callosum, cerebral white matter atrophy, and developmental disorders (Table 1). This information can aid in the differential diagnosis of patients presenting with craniofacial abnormalities. Notably, advances in genetic technologies now enable precise identification of pathogenic mutations, offering opportunities for early molecular diagnosis and genetic counseling to facilitate informed reproductive decisions and improve family outcomes.

Table 1.

Clinical features in desmosterolosis

Feature	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9	Case 10	Case 11	Case 12
Sex	F	M	M	F	M	F	F	F	F	M	M	F
Survival	N	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Ancestry	European	European	Israeli Bedouin	Israeli Bedouin	Israeli Bedouin	Israeli Bedouin		Middle Eastern	Middle Eastern	Middle Eastern	Pakistani	Italian
Facial Anomaly
Cleft palate	Y	Y						Y	N	Y
Gingival nodules	Y
Nasal hypoplasia	Y	N
Macrocephaly	Y	N					Y					Y
Microcephaly		Y	Y	Y	Y	Y				Y
Micrognathia		Y	Y	Y	Y	Y	Y	Y	N	Y		Y
Downslanting PF		Y								Y		Y
Prominent forehead							Y
Short nose							Y
Anteverted nares							Y					Y
Telecanthus							Y
Low set ears	Y							Y	Y	Y
Bitemporal narrowing								Y	Y	N
Neurological
Nystagmus			Y	N	Y	Y		Y	Y			Y
Strabismus			Y	N	Y	Y		Y	Y	Y		Y
Immature gyri	Y						Y
ACC		Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
Ventriculomegaly			Y	Y	Y	Y		Y	Y	Y	Y
Thinning of WM			Y	Y	Y	Y		Y	Y	N	Y
Hydrocephalus							Y			Y
Absent septum pellucidum							Y
Optic atrophy/ Visual impairment								Y	Y			Y
Hearing loss								Y			Y	N
Seizure			Y	Y	Y			Y	Y	N	N	Y
Limb & skeletal
Osteoslerosis	Y	N								N
Arthrogryposis		Y	Y	Y	Y	Y	Y	Y	Y	Y	N
Bilateral clubfeet		Y						Y	Y	Y
Syndactyly	N						Y			N
Rhizomesomelia							Y
Muscle wasting								Y	Y
Urogenital anomalies	Y	Y								Y	Y
Cardiac defect										N
CHD	Y										Y
Persistent PDA		Y									Y
Cutis aplasia		Y
Hirsutism								Y	Y
Growth tardation	-	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y

Abbreviations: PF Palpebral fissures, ACC Agenesis of the corpus callosum, WM White matter, CHD Congenital heart disease, PDA Patent ductus arteriosus

References: Case1: FitzPatrick et al., 1998 [48], Case2: Andersson et al., 2002 [49], Case3-6: Zolotushko et al., 2011 [50], Case7: Schaaf et al., 2011 [51], Case8-9: Dias et al., 2014 [52], Case10: Rohanizadegan and Sacharow, 2018 [53], Case11: Hill et al., 2023 [54], Case12: Cocciadiferro et al., 2023 [55]

DHCR24 in neurological disorders

A growing body of epidemiological and molecular evidence underscores the inextricable relationship between cholesterol homeostasis and the pathogenesis of neurological disorders [56–61]. Within this context, DHCR24, a pivotal rate-limiting enzyme in cerebral cholesterol biosynthesis, plays a central role in maintaining sterol equilibrium. Its critical importance is highlighted by the fact that loss-of-function mutations in DHCR24 lead to desmosterolosis, a rare neurodevelopmental disorder characterized by the pathological accumulation of desmosterol, although some scholars contend that moderate elevations of this metabolic intermediate may not invariably precipitate severe clinical outcomes [50]. The relevance of DHCR24 to common neurodegenerative disorders was unequivocally established by the seminal finding of its marked downregulation in the temporal cortex of AD patients [1]. Subsequent neuropathological investigations corroborated that this downregulation correlates specifically with neuronal degeneration rather than Aβ plaque deposition, pointing to the potential existence of an amyloid-independent pathway in AD pathogenesis [62]. The functional role of DHCR24 in the central nervous system, however, is not simply one of sterol production, but exhibits a complex dichotomy. Intriguingly, research by Kuehnle et al. has illuminated its context-dependent roles under oxidative stress, demonstrating that low levels of DHCR24 can confer cytoprotection via p53-mediated antioxidant pathways, whereas elevated levels exert neuroprotective effects through cholesterol-dependent membrane stabilization [63]. This bifunctional nature is further supported by work from Susanna Benvenuti et al., who identified DHCR24 as a critical mediator of the neuroprotective actions of estrogen and SERMs in human neuronal models [64]. Collectively, these studies posit that DHCR24 operates as a dynamic guardian, adapting its protective strategy to metabolic and oxidative challenges. In stark contrast to these protective roles, emerging evidence suggests that DHCR24 may also mediate cell death under specific pathological conditions. Notably, under severe oxidative stress or during apoptotic cascades, DHCR24 undergoes proteolytic cleavage to generate a 40-kDa fragment (P40) [1], which has been implicated in pro-apoptotic activity. This duality creates a compelling paradox, particularly in the context of AD: does the observed downregulation of DHCR24 represent a loss of its essential neuroprotective functions, or could it also be a consequence of, or even a contributor to, a pathological shift towards its pro-apoptotic state? Given the divergent and occasionally contradictory functional descriptions of DHCR24 in the nervous system, ranging from cholesterol homeostasis maintenance to oxidative stress modulation and apoptosis regulation, this review will critically delineate the precise roles and mechanistic underpinnings of DHCR24 in neurological disorders. Furthermore, we will evaluate its potential as a therapeutic target, specifically examining its dual implications in pathogenesis and therapy.

Alzheimer’s disease

Alzheimer’s disease represents a progressive neurodegenerative disorder of the central nervous system characterized by deteriorating cognitive function and behavioral impairments [65]. The core clinical manifestations encompass memory deficits, aphasia, apraxia, agnosia, visuospatial dysfunction, and personality/behavioral alterations [66–69]. Currently, AD has emerged as a critical global challenge impacting public health and sustainable societal development. Histopathological hallmarks include neuritic plaques, neurofibrillary tangles, neuronal loss, and glial proliferation [70–74]. Despite decades of intensive investigation, the pathogenic mechanisms underlying this condition remain incompletely elucidated, with numerous critical questions still unresolved. Investigating the relationship between lipid metabolism and AD represents a breakthrough in understanding AD mechanisms while simultaneously providing viable strategies for therapeutic intervention [75]. And among these, the precise role of DHCR24 represents a particularly compelling and enigmatic aspect worthy of further exploration.

Following the seminal discovery by Greeve et al. identifying DHCR24 as one of the significantly downregulated genes among 30 candidates in vulnerable brain regions of AD patients, subsequent investigations by independent research groups have substantiated that DHCR24 gene polymorphisms modulate AD susceptibility, thereby implicating DHCR24 as a potential risk modifier in AD pathogenesis [76]. Notably, Hosseinzadeh et al. provided critical temporal insights using a streptozotocin-induced rat model of cognitive decline, demonstrating that hippocampal DHCR24 downregulation occurs as early as 14 days post-induction, preceding the onset of detectable cognitive impairment, and correlates with both neuronal loss and behavioral deficits [77]. Nevertheless, the precise mechanistic underpinnings linking DHCR24 dysregulation to AD progression remained unresolved. During this period, a research team at the University of Florence, Italy, systematically investigated the interplay between DHCR24 and endocrine hormones, with particular emphasis on estrogen and SERMs. Their initial hypothesis posited DHCR24 as a critical mediator of estrogen-induced neuroprotection. Methodologically, small interfering RNA (siRNA)-mediated silencing of DHCR24 in FNC cells (silFNC) demonstrated markedly reduced DHCR24 protein expression compared to both untransfected FNC and control siRNA-treated cells (control silFNC). Notably, 17β-estradiol (17β-E2) treatment in silFNC cells exhibited diminished efficacy in counteracting Aβ toxicity and oxidative stress, concomitant with elevated caspase-3 activation. Crucially, bioinformatic analysis revealed high sequence homology (79.3%-97%) between the upstream regulatory region of the DHCR24 promoter and two established estrogen-responsive elements. This study constituted the first empirical evidence globally that DHCR24 serves as an obligatory intermediary for the neuroprotective effects of both estrogen and SERMs, mechanistically achieved through direct transcriptional activation via semi-palindromic estrogen response sequences in the DHCR24 promoter [78]. Complementing these findings, a separate investigation the following year demonstrated that DHCR24 downregulation potentiates caspase-3 activity, leading to golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein (GGA3) depletion and consequent elevation of β-secretase 1 (BACE1) levels and enzymatic activity. This cascade not only reinforced the pathophysiological relevance of DHCR24 in AD but also nominated it as a tractable therapeutic target for disease modification [79].

In the following decade, few studies focused on the relationship between DHCR24 and the pathogenesis of AD until 2020, when a Turkish research team analyzed serum samples from healthy controls, pure AD patients, and AD patients comorbid with diabetes [80]. They found that serum DHCR24 levels in pure AD patients showed no significant difference compared to controls, whereas AD patients with diabetes exhibited markedly reduced DHCR24 levels, which were negatively correlated with blood glucose levels. Thus, the researchers proposed that both DHCR24 and glucose dysregulation may contribute to AD development. However, the causal relationship remains unclear and requires further experimental validation. Interestingly, Simpson et al. provided a nuanced perspective from human neuropathology, reporting that in early Braak stage (0–II) cortices, neurons with high DNA damage response actually exhibited upregulation of DHCR24 alongside other cholesterol synthesis enzymes such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) [81]. This suggests a potential compensatory activation of the cholesterol biosynthesis pathway in response to oxidative stress during the earliest phases of Alzheimer-type pathology. Ting Liu et al. demonstrated that pharmacological inhibition of DHCR24 using U18666A led to reduced intracellular cholesterol levels and impaired caveolar function in brain cells, which was attributed to dysregulation of the Insulin/IGF-1/protein kinase B (Akt) signaling pathway [82]. These findings hold significant implications for the evolving theoretical framework of neurodegenerative disorders. Experimentally validated disruptions in insulin-sensitive metabolic pathways provide compelling evidence supporting the conceptualization of AD as “Type 3 Diabetes”. This conclusion not only bridges the long-standing disciplinary divide between neurology and endocrinology but also establishes a critical theoretical foundation for future multidisciplinary and cross-system investigations into disease mechanisms.

Despite its initial discovery in the context of AD and subsequent sporadic studies, research on DHCR24 remained fragmented and failed to coalesce into a coherent model. A turning point was reached in 2020, a research team from Fudan University in China has recently directed its investigative focus toward this pivotal molecule. In their initial experiments, employing in vitro overexpression of DHCR24, they elucidated its capacity to exert potent anti-inflammatory effects via modulation of the Akt/GSK3β signaling cascade, thereby facilitating the phenotypic transition of microglia from the pro-inflammatory M1 state to the neuroprotective M2 polarization state [83]. Subsequent investigations utilizing lentiviral transduction in SH-SY5Y neuroblastoma cells revealed that targeted knockdown of DHCR24 expression precipitated pathological hyperphosphorylation of multiple microtubule-associated protein tau (tau) protein epitopes, including critical residues Thr181, Thr231, Ser262, Ser396, and Ser422, whereas DHCR24 overexpression conversely suppressed this aberrant phosphorylation pattern. Moreover, these manipulations of DHCR24 expression levels were found to concomitantly elevate cellular membrane cholesterol content and upregulate caveolin-1 expression, thereby fostering the biogenesis of lipid rafts/caveolae. Mechanistic dissection further demonstrated that these pleiotropic effects were mediated through DHCR24’s regulatory influence on both protein phosphatase 2 A (PP2A) and GSK3β enzymatic activities. Strikingly, parallel experiments conducted in astrocytic models recapitulated these phenomena upon DHCR24 knockdown or overexpression, albeit through a distinct mechanistic paradigm, that is to say, the bidirectional modulation of lipid raft-dependent rat sarcoma viral oncogene homolog/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Ras/MEK/ERK) signaling pathway activation, thereby underscoring the cell type-specific orchestration of DHCR24’s neurobiological functions [84, 85]. Given that GSK3β serves as a master regulator of tau phosphorylation, capable of phosphorylating tau at virtually every relevant epitope, the research team specifically interrogated tau kinase dynamics in this context. Their investigations revealed that DHCR24 knockout-induced tau hyperphosphorylation was mechanistically dependent upon the potentiation of the GSK3β/mechanistic target of rapamycin (mTOR) signaling axis within the broader phosphatidylinositol 3-kinase (PI3-K)/Akt pathway [86]. Based on their foundational work in tauopathy, the research team subsequently expanded their focus to elucidate the role of DHCR24 in AD-associated synaptopathy. The researchers employed a lentivirus-mediated knockdown approach to deplete DHCR24, which initiated a well-defined sequence of molecular events. This intervention first led to a significant decrease in intracellular cholesterol levels. The cholesterol deficiency subsequently impaired the phosphorylation and activation processes of calmodulin-dependent protein kinase 2 (CaMK-Ⅱ), a pivotal enzyme for synaptic signaling. The inhibition of CaMK-Ⅱ activity ultimately resulted in a substantial disruption of synaptosome motility. Although this experimental model utilized the SH-SY5Y neuroblastoma cell line and therefore cannot fully recapitulate the intricacies of the in vivo physiological environment, these findings nonetheless collectively delineate a novel molecular mechanism linking cholesterol metabolism to synaptic pathology, with DHCR24 operating through the CaMK-Ⅱ/Synapsin-1 pathway as a critical molecular event in AD progression [87].

The pathogenesis of AD remains incompletely understood. In addition to the hyperphosphorylation of tau protein, the deposition of Aβ is also implicated. However, the role of Aβ deposition remains controversial. While the predominant view suggests that elevated cholesterol levels contribute to increased Aβ accumulation, some studies present opposing evidence, proposing instead that reduced cholesterol levels may lead to Aβ upregulation [88–90]. Yue Huang et al. established a novel cellular model by knocking down DHCR24, demonstrating that cholesterol reduction induced by DHCR24 deficiency promotes Aβ deposition [91]. Furthermore, their adenovirus-mediated DHCR24 knock-in in 5×FAD mice, a model characterized by low cholesterol and DHCR24 expression, attenuated cholesterol loss and reversed AD-related pathological manifestations, including Aβ accumulation, synaptic impairment, dysregulated autophagy, microglial phagocytosis dysfunction, and apoptosis [92]. These findings provide compelling evidence supporting DHCR24 as a therapeutic target for neurodegenerative diseases with pathological hallmarks such as tau hyperphosphorylation and Aβ deposition, offering new translational perspectives. Disruption of cerebral cholesterol metabolism has been implicated in the pathogenesis of neuropsychiatric disorders including anxiety and depression. Concurrently, neuropsychiatric syndrome (NPS) in AD significantly contributes to overall clinical deterioration [8, 93]. Based on these established connections, Gong and colleagues investigated depression-like behaviors in AD [94]. They pioneered the development of a novel 5xFAD mouse model overexpressing human apolipoprotein E4 (ApoE4). Through behavioral assessments including open field and Morris water maze tests, they demonstrated that ApoE4 exacerbates anxiety and depression-like behaviors while worsening cognitive deficits. Biochemical analyses revealed elevated LDL-C and reduced HDL-C in peripheral blood, decreased cholesterol levels in the prefrontal cortex, and downregulation of DHCR24, a key cholesterol synthase. The authors proposed that these neuropsychiatric manifestations might be associated with dysregulation of the DHCR24/GSK3β/mTOR and postsynaptic density protein 95 (PSD95)/CaMK-Ⅱ/brain-derived neurotrophic factor (BDNF) signaling pathways. However, the study did not elucidate the specific molecular targets through which ApoE4 modulates lipid metabolism. Despite this limitation, their findings provide valuable insights into potential therapeutic targets for managing depression in AD.

Research on DHCR24 and AD extends beyond fundamental investigations. In a multi-tissue epigenomic study by Sarnowski et al., an epigenome-wide association study (EWAS) of patient blood samples identified a connection between insulin resistance (IR) and AD [95]. This association was subsequently validated in dorsolateral prefrontal cortex tissue from the Rush Memory and Aging Project and Religious Orders Study cohort. The analysis identified several DNA methylation markers significantly associated with homeostatic model assessment for insulin resistance (HOMA-IR), including cg17901584, located near the DHCR24 gene, which was linked to lower IR and has known roles in cholesterol synthesis. Although blood-derived DHCR24 methylation showed a strong association with insulin resistance, with a particularly pronounced effect in females, no significant correlations emerged with neurological outcomes including dementia status or brain volume measurements in the Framingham Heart Study (FHS) cohort. Similarly, this epigenetic marker demonstrated no association with AD pathology in the rush memory and aging project and religious orders study cohort. These findings collectively suggest that DHCR24 methylation operates through a peripheral-specific epigenetic mechanism primarily involved in metabolic regulation rather than direct neuropathological processes. In contrast, two CpG sites in the carnitine palmitoyltransferase 1 A (CPT1A) gene exhibited tissue-divergent effects: higher blood methylation was associated with lower insulin resistance and more favorable brain volume measures, whereas higher brain methylation correlated with increased AD risk and pathology. These findings highlight DHCR24 and CPT1A as key loci where epigenetic regulation may distinctly influence metabolic and neurodegenerative pathways. However, the study is limited by its focus on individuals of predominantly European ancestry, restricting generalizability, and the lack of glycemic or insulin resistance measures in the brain tissue cohort, which precludes direct assessment of brain-specific insulin resistance. Additionally, the correlative nature of the findings warrants further mechanistic studies to establish causality and tissue-specific regulatory dynamics.

Beyond fundamental and population-based studies, attempts in pharmaceutical development have been progressively advancing. Aghajanzadeh et al. developed a nanoparticle formulation of baicalein and administered it to AD model mice to evaluate its therapeutic potential [96]. Their findings demonstrated that this nano-drug improved learning and memory functions in cognitively impaired mice. The authors proposed that this therapeutic effect might correlate with upregulation of DHCR24, SELADIN, and sirtuin 6 (SIRT6) in the hippocampal region. However, the study did not further elucidate the specific mechanisms or underlying relationships involved in this regulatory process. Complementing these findings, further experimental evidence supports the central role of DHCR24 in neuroprotective pathways. Experimental studies have demonstrated that the antidepressant agomelatine can suppress Aβ deposition, tau protein hyperphosphorylation, and neuroinflammatory responses in the hippocampus of APP/presenilin 1 (PS1) mice. This neuroprotective effect is achieved through activation of the DHCR24 signaling pathway while simultaneously inhibiting both the Akt/mTOR and Hes family bHLH transcription factor 1/Notch receptor 1 (Hes1/Notch1) signaling pathways [97]. In summary, accumulating evidence strongly suggests that DHCR24 represents a highly promising molecular target for AD therapy, owing to its multifaceted mechanisms of action (Fig. 5). Consequently, targeted upregulation of DHCR24 expression in brain regions may serve as a viable therapeutic strategy to modulate the pathogenic cascade of AD.

Fig. 5.

Signaling pathway of DHCR24 in Alzheimer’s disease (AD). Left panel: AD-related signaling pathways following DHCR24 suppression (inhibition/knockout). Right panel: Pathways regulated by DHCR24 overexpression in AD. P: phosphorylation. Figure created with BioRender. (GGA3: Golgi-localized γ-ear-containing ADP-ribosylation factor-binding Protein, BACE1: β-secretase 1, Akt: protein kinase B, GSK3β: glycogen synthase kinase 3β, tau: microtubule-associated protein tau, PP2A: protein phosphatase 2 A, Ras: rat sarcoma viral oncogene homolog, MEK: mitogen-activated protein kinase kinase, ERK: extracellular signal-regulated kinase, mTOR: mechanistic target of rapamycin, PI3-K: phosphatidylinositol 3-kinase, Hes1: hes family bHLH transcription factor 1, Notch1: notch receptor 1)

Huntington’s disease

Huntington’s disease (HD), also known as Huntington chorea, is an autosomal dominant neurodegenerative disorder affecting the basal ganglia and cerebral cortex. Clinically, it is characterized by insidious onset and progressive deterioration, manifesting as chorea, psychiatric disturbances, and dementia [98–100]. The disease typically shows no gender predilection, but exhibits a clear association with age, a pattern primarily attributable to its underlying pathogenic mechanisms [101–103]. The primary pathological manifestation involves abnormal expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin protein (HTT) gene located on chromosome 4 (4p16.3). Typically, pathological alleles exceed 40 CAG repeats. The misfolding and aggregation of mutant HTT (mHTT) trigger widespread cellular and metabolic dysfunction, ultimately leading to neurodegeneration [104–106]. Currently, no disease-modifying therapies have received regulatory approval for the treatment of HD [107]. Since DHCR24 was first implicated in AD, its neuroprotective effects have attracted increasing research attention. HD, a neurodegenerative disorder intricately linked to aberrant lipid metabolism [108, 109], is now increasingly recognized to exhibit a compelling association with DHCR24, as evidenced by a growing body of experimental and clinical studies. Employing GC-MS/MS technology, Kreilaus et al. systematically analyzed the dynamic alterations of cholesterol precursors, metabolites, and oxidized products in the striatum and cortex of R6/1 transgenic HD mouse models across 6 to 28 weeks of age, integrating complementary behavioral tests to investigate the role of cholesterol metabolic dysregulation in disease progression [110]. Their results revealed a significant elevation in desmosterol levels during the late disease stages (20 and 28 weeks), suggesting potential impairment of DHCR24 activity, the key enzyme responsible for its conversion to cholesterol, thereby leading to desmosterol accumulation. Furthermore, striatal levels of cholesterol metabolites 24-hydroxycholesterol and 27-hydroxycholesterol were also markedly reduced. However, the study did not directly measure DHCR24 enzymatic activity or protein expression, nor did it explore the underlying regulatory mechanisms. Consequently, the precise causes of DHCR24 functional alterations and their causal contributions to neurodegeneration in HD remain incompletely understood, representing critical knowledge gaps that warrant further investigation. A. Samara et al. established an in vitro HD model using ST14A cells with stable low expression of the HTT gene, complemented by animal models (R6/2 HD transgenic mice) and human HD tissue samples [111]. Their investigation of DHCR24 expression at both RNA and protein levels revealed decreased DHCR24 during symptomatic phases in cellular and animal models. Interestingly, elevated expression was observed in pre-symptomatic animal models and human samples—a discrepancy potentially attributable to limited human sample size (only three cases each for control and experimental groups), inconsistent sampling timelines, and possible confounding effects from astrocyte proliferation in HD patient brain tissues. Subsequently, F. Kreilaus et al. conducted regional analyses of brain tissues from 13 HD patients and non-HD controls, revealing significantly reduced DHCR24 expression in HD patients, with the most pronounced decrease observed in the putamen [112]. Years later, the work of Pinchaud et al. has once again linked DHCR24 to HD, prompting renewed focus on its potential role in this disorder. The researchers elucidated the cell-specific mechanisms by which neuronal restoration of cytochrome P450 family 46 subfamily A member 1 (CYP46A1) modulates cholesterol homeostasis in the striatum of zQ175 HD mice. CYP46A1 is involved in the catabolic metabolism of cholesterol within neurons, where it catalyzes the conversion of cholesterol to 24(S)-hydroxycholesterol (24 S-OHC). In patients with HD, plasma levels of 24 S-OHC are notably reduced, and this reduction parallels the degree of caudate nucleus atrophy observed in these individuals [113, 114]. Hence, using in situ hybridization and immunostaining, the authors demonstrated that adeno-associated virus (AAV)-mediated CYP46A1 re-expression in neurons exerted a bimodal effect. It directly upregulated key cholesterogenic genes, including the critical enzyme DHCR24, HMGCR, and the transcription factor SREBP2, specifically within neurons, indicating a reactivation of local cholesterol synthesis. Conversely, CYP46A1 expression induced a paracrine upregulation of the cholesterol efflux gene ApoE exclusively in astrocytes, likely mediated by its oxysterol product 24 S-hydroxycholesterol [115]. This study faces limitations due to technical difficulties in co-staining experiments and an analytical approach that restricts its focus to neurons and astrocytes while overlooking other glial populations, along with its dependence on a single Huntington disease mouse model which may not fully represent the pathological spectrum of disease progression. Nevertheless, the findings strongly support CYP46A1 as a promising therapeutic target for addressing cell type specific cholesterol dysregulation in Huntington disease. These findings provide substantive evidence supporting DHCR24’s involvement in the pathogenesis and progression of HD, and we anticipate these discoveries will contribute significantly to future therapeutic breakthroughs against this devastating disorder.

Cerebrovascular disease

Ischemic stroke

Although DHCR24 has primarily been studied in the context of neurodegenerative diseases, particularly AD, growing evidence now highlights its role in ischemic stroke. Based on the shared pathological features between ischemic stroke and AD, including neuroinflammation, Aβ deposition, and elevated calcium levels, the non-selective calcium channel blocker bepridil has emerged as a candidate therapeutic [116–118]. Researchers at the Institute of Clinical Medicine, University of Eastern Finland, administered oral bepridil to rats subjected to middle cerebral artery occlusion (MCAO). They observed significantly reduced Aβ deposition and calcium levels in the ipsilateral thalamus of treated animals compared to the model group, while no significant differences were detected in the contralateral hemisphere. More importantly, treatment with bepridil restored DHCR24 mRNA and protein levels and improved motor function in stroke model rats. Although the team did not elucidate the underlying mechanism responsible for this phenomenon, their findings nonetheless offer promising therapeutic potential for ischemic stroke and establish a critical link between DHCR24 and ischemic stroke pathology for the first time [119].

While these drug-based approaches revealed therapeutic potential, the research focus has progressively shifted toward elucidating the direct role of DHCR24 in stroke pathogenesis. Macarena et al. were the first to investigate DHCR24 in a permanent ischemic stroke model in mice, demonstrating that its neuroprotective effect is mediated through the association of the excitatory amino acid transporter 2 (EAAT2) glutamate transporter with lipid rafts [120]. The following year, another team induced striatal DHCR24 overexpression in mice prior to transient middle cerebral artery occlusion (tMCAO) modeling and found that DHCR24 overexpression significantly reduced infarct volume, though without significant changes in inflammatory markers [121]. This finding contrasts with Macarena et al., who observed increased levels of both pro- and anti-inflammatory cytokines 24 h post-MCAO in DHCR24+/- mice [120]. Collectively, these findings underscore the emerging role of DHCR24 in ischemic stroke, revealing its dual involvement in both neuroprotective and neuroinflammatory processes. While DHCR24 appears to regulate critical pathways such as glutamate transporter trafficking via lipid rafts and calcium-mediated Aβ pathology, the mechanistic details remain partially elusive, particularly regarding its context-dependent modulation of inflammation. Further studies are warranted to dissect the molecular cascades downstream of DHCR24 and evaluate its therapeutic potential in cerebral ischemia.

Cerebral small vessel disease

Cerebral Small Vessel Disease (CSVD) is a leading cause of vascular cognitive impairment [122]. Nevertheless, the fundamental pathological mechanisms driving cerebral small vessel disease-related cognitive impairment (CSVD-CI) remain incompletely understood [123]. CSVD involves chronic injury to the neurovascular unit (NVU), including endothelial cells, pericytes, and astrocytes, which collectively maintain BBB integrity and neurovascular coupling [124]. NVU disruption, oxidative stress, and inflammatory activation are recognized hallmarks of both CSVD and ischemic stroke, which share a vascular inflammatory basis for cognitive decline [125].

Furthermore, the current diagnostic landscape lacks robust early detection capabilities, as existing approaches rely primarily on conventional CSVD markers while demonstrating a notable absence of validated biomarkers or advanced neuroimaging indicators for premorbid identification [126, 127]. Recent advances in RNA and lipid biology have emphasized that endothelial and pericyte dysfunction are not merely structural consequences but are transcriptionally regulated by lipid metabolism and noncoding RNAs [128, 129]. Shi and colleagues conducted a cohort study including both cognitively normal individuals and CSVD-CI patients [130]. Using RNA-sequencing (RNA-seq) technology to screen for differentially expressed genes, they identified decreased expression of DHCR24 and its upstream regulator, hsa_circ_0015335, in CSVD-CI patients, which was correlated with cholesterol metabolism. This finding provides a novel perspective on the role of circRNA in regulating cholesterol metabolism during cognitive impairment and suggests a potential biomarker for the early diagnosis of CSVD-CI. It should be noted, however, that the cohort was recruited solely from Wuxi People’s Hospital and the sample size was limited. Future multi-center, large-sample studies are therefore warranted, along with mechanistic validation using animal models. Importantly, the link between lipid metabolism, endothelial protection, and inflammation is further supported by recent findings showing that activation of endothelial peroxisome proliferator-activated receptor γ (PPARγ) signaling by nitro-oleic acid (OA-NO₂) alleviates neurovascular injury and improves functional recovery after ischemic stroke [39]. Despite these methodological limitations, the pioneering nature of Shi et al.‘s work remains noteworthy. Nonetheless, this study is the first to reveal the role of DHCR24 and its upstream circRNA in CSVD-CI. Given the current strong research focus on cognitive impairment in neurological disorders, these results hold significant relevance and lay a foundation for further investigation into CSVD-CI and the development of targeted therapies.

Other neurological disorders

Spinal cord injury

Spinal cord injury (SCI), typically caused by traumatic or non-traumatic events, is classified into primary and secondary injury phases [131, 132]. This condition results in complete or incomplete loss of sensory and motor functions below the level of injury [133, 134]. Since primary injury is largely irreversible, current therapeutic strategies primarily target secondary injury to mitigate edema, inflammation, and other pathological processes [135, 136]. Given the limited treatment options, Hong Zeng et al. adopted an innovative approach by investigating the relationship between cholesterol metabolism and SCI pathology using a ketogenic diet (KD) combined with RNA-seq bioinformatics analysis [137]. Their results demonstrated significant upregulation of cholesterol metabolism-related genes, including DHCR24, in KD-treated SCI model mice. This finding indicates that KD can transcriptionally reprogram steroid metabolism during SCI recovery, potentially facilitating remyelination and improving neurological function. In summary, this study highlights the therapeutic potential of modulating cholesterol metabolism for functional recovery after SCI. With the advancement of RNA-seq technology, Chang et al. also utilized this approach to investigate genes regulated in SCI. However, unlike Hong Zeng et al., who employed a ketogenic diet model, this group mimicked human SCI by inserting the tip of a 5 mm surgical forceps into both sides of the spinal cord at the T9-T10 vertebral level in Sprague-Dawley (SD) rats. Using this animal model, they examined gene expression changes at 1 day and 21 days post-injury (dpi). They observed a downregulation of DHCR24 after injury, which was more pronounced at 21 dpi than at 1 dpi [138]. The authors proposed that focusing on these downregulated genes could provide valuable insights for promoting repair and regeneration following SCI. Since the researchers based their findings solely on transcriptomic analysis without subsequent in vivo functional validation, we propose that future studies should employ gain-of-function (e.g., overexpression) or loss-of-function (e.g., gene knockout) approaches to elucidate the precise role and mechanisms of DHCR24 in SCI. Such investigations would not only clarify whether DHCR24 expression is indeed upregulated or downregulated post-SCI but also facilitate the development of targeted neuroprotective and regenerative strategies. Regarding the contradictory results between the two research groups, we speculate that the discrepancy likely stems from the different modeling methodologies. Given that Chang’s model more closely replicates the biomechanics of human traumatic SCI, we consider their transcriptomic data to be relatively more reliable. Nevertheless, these findings open up promising avenues for targeting metabolic pathways as part of a multifaceted strategy to mitigate secondary damage and enhance outcomes in SCI.

Traumatic brain injury

Traumatic brain injury, which constitutes a severe medical condition resulting from external forces such as vehicular accidents or violent impacts, encompasses both primary injury and subsequent tissue and cellular damage, known as secondary injury [139–142]. However, the pathophysiological mechanisms underlying secondary injury remain incompletely understood. It is well-established that intracranial hypertension and cerebral edema frequently occur post-traumatic brain injury, where steroids can mitigate edema and improve neurological outcomes [143, 144]. Traumatic brain injury can affect digestive function through inflammatory immune responses, the enteric nervous system, and hormonal levels, and conversely, digestive dysfunction can exacerbate neurological injury via bidirectional communication along the brain-gut axis [145]. Beyond these systemic interorgan interactions, recent research has begun to unravel the intrinsic molecular mechanisms within the brain that underlie neurological protection and repair. A recent study has elucidated a key downstream mechanism through which triggering receptor expressed on myeloid cells 2 (TREM2) alleviates white matter injury after traumatic brain injury, namely by regulating DHCR24 to activate the LXR pathway [146]. The study found that loss of TREM2 leads to aberrant upregulation of DHCR24 expression in microglia, which subsequently suppresses the activation of LXR and its downstream cholesterol transport genes (such as ATP-binding cassette transporter A1 (Abca1) and ATP-binding cassette transporter G1 (Abcg1)). This ultimately impairs cellular phagocytic function and cholesterol metabolism, exacerbating myelin damage and hindering the regeneration and repair of oligodendrocytes. Conversely, pharmacological upregulation of TREM2 effectively suppressed DHCR24, thereby restoring beneficial LXR signaling, which promoted white matter integrity and neurological functional recovery. This work establishes for the first time that DHCR24 is a crucial effector molecule in TREM2-mediated neuroprotection, revealing the TREM2/DHCR24/LXR pathway as a potential therapeutic target for white matter injury after traumatic brain injury.

Multiple sclerosis

Multiple sclerosis is a chronic autoimmune neurological disorder characterized by inflammatory demyelination, with a predominant onset in young adults [147, 148]. Currently, no curative approaches are available for this condition, and consequently, existing disease-modifying therapies such as interferon-beta (IFN-β) primarily focus on mitigating inflammatory responses; however, they remain incapable of reversing demyelination or repairing neuronal damage [149]. Cholesterol metabolic dysregulation has been closely implicated in the pathological progression of multiple sclerosis [150]. Building upon previous findings, Yang et al. evaluated the therapeutic potential of Analgecine (AGC) in experimental autoimmune encephalomyelitis (EAE) mice, a well-established multiple sclerosis model. Their results demonstrated that AGC treatment enhanced the expression of myelin-related markers and reduced neuronal loss, suggesting a protective effect on myelin integrity and attenuation of white matter injury. Furthermore, molecular docking analysis indicated that the neuroprotective function of AGC is achieved through binding to DHCR24 [151]. While this study establishes a correlation between AGC-induced neuroprotection and DHCR24 upregulation, the precise mechanistic pathway remains undefined. In particular, the lack of interventional approaches, such as DHCR24 knockdown or knock-in studies, precludes definitive conclusions regarding causal involvement. Thus, comprehensive mechanistic studies and functional validation are warranted to fully elucidate the role of DHCR24 in this context. This study demonstrates considerable innovation by establishing a previously unrecognized link between an existing pharmaceutical compound and multiple sclerosis pathology. This approach holds significant promise for accelerating clinical translation, as the repurposing of already approved drugs can substantially shorten the developmental timeline. Furthermore, the identified agent shows potential for integration into combination therapies with established multiple sclerosis treatments, possibly leading to enhanced therapeutic synergy. Beyond its immediate applications, this investigation provides a conceptual framework that could guide future exploration of existing drugs, thereby expanding the scope of drug repositioning strategies in clinical science, not only in neuroscience.

Spinocerebellar ataxia type 2

Spinocerebellar ataxia type 2 (SCA2) represents the most severe subtype of spinocerebellar ataxia and ranks as the second most common form within this disease category [152, 153]. As an autosomal dominant cerebellar ataxia, SCA2 results from an abnormal expansion of CAG repeats in the coding region of the ataxin 2 (ATXN2) gene located at chromosome 12q23-q24.1 [154–156]. The condition primarily features truncal ataxia, dysarthria, and slowed saccadic eye movements, with less frequent manifestations including ophthalmoparesis and chorea [156, 157]. Building upon the established clinical characteristics and genetic basis of SCA2, researchers have delved deeper into its molecular pathological mechanisms, with particular focus on the role of abnormal cholesterol metabolism in disease progression. Emerging evidence has revealed that disrupted lipid metabolism may be intricately linked to multiple aspects of neurodegenerative processes. These insights have provided a novel perspective for understanding the pathogenesis of SCA2. Against this research backdrop, Júlia Canet-Pons et al. employed Atxn2-CAG100-knockin mice to model human SCA2 pathology [158]. Their investigation revealed that polyglutamine (polyQ) expansion in the ATXN2 gene triggers toxic RNA accumulation, subsequently activating the Toll-like receptor 7/receptor-interacting serine/threonine-protein kinase 1 (TLR7/RIPK1) pathway and promoting caspase-3 mediated cytoplasmic retention of TAR DNA-binding protein 43 (TDP43). Simultaneously, deficiency in DHCR24, a crucial cholesterol synthase, substantially reduced cholesterol and its precursors, thereby establishing a direct connection between cholesterol metabolism and SCA2 pathogenesis. These findings offer novel therapeutic directions and potential targets for related disorders. However, the study lacks interventional experiments to validate this proposed target. Furthermore, researchers have not yet confirmed alterations in cholesterol metabolism within spinal cord specimens from human SCA2 patients so far. Future studies should address these limitations to strengthen the proposed mechanism and explore its therapeutic potential.

Pituitary adenomas

Pituitary adenomas represent a heterogeneous group of intracranial tumors originating from adenohypophyseal cells, constituting approximately 15% of all diagnosed intracranial neoplasms [159, 160]. While frequently classified as benign lesions, these tumors can lead to significant clinical sequelae through mass effects on adjacent neurovascular structures and dysregulation of pituitary hormone secretion. The molecular pathogenesis of pituitary tumorigenesis involves complex interactions between genetic predisposition and metabolic alterations, with recent evidence highlighting the crucial role of cholesterol homeostasis in this process [161, 162]. Specifically, aberrant cholesterol metabolism has been shown to influence multiple aspects of tumor biology, including cellular proliferation, apoptosis resistance, and hormone production, thereby establishing a compelling rationale for investigating key cholesterol metabolic enzymes in this context [163, 164]. DHCR24 has been confirmed to be expressed in normal pituitary tissue. Building on this finding, Paola Luciani et al. demonstrated that DHCR24 is highly expressed in non-functioning pituitary adenomas compared to growth hormone (GH)-secreting adenomas [165]. Their study suggests that in GH-secreting adenomas, DHCR24 may exert therapeutic effects by suppressing caspase-3 activation. This discovery could potentially overcome the limitations of conventional pharmacological treatments for pituitary adenomas and their associated adverse effects. If successfully translated into clinical practice, this approach may offer significant benefits for patients.

Collectively, accumulating evidence indicates that DHCR24 participates in multiple aspects of the pathophysiology of neurological disorders, establishing its crucial role in maintaining neuronal homeostasis through both metabolic and non-metabolic mechanisms. Obviously, DHCR24 has emerged as a significant neuroprotective factor and a master regulator of metabolic reprogramming in various disease contexts. Its functional importance extends across a broad spectrum of neurological and neuroendocrine disorders, with compelling evidence supporting its therapeutic potential in conditions ranging from acute insults to chronic degenerative processes. Moreover, the significance of DHCR24 extends well beyond classical neurodegenerative diseases to encompass acute neurological injuries such as cerebral ischemia and spinal cord trauma. Findings from diverse injury models collectively suggest that DHCR24 may represent a common protective mechanism across various forms of neural damage (Fig. 6). Research on neuroinflammatory conditions, particularly multiple sclerosis and its animal models, has further validated the therapeutic potential of DHCR24, positioning it as a unique target for comprehensive intervention in neuroinflammatory disorders. Simultaneously, discoveries in the neuroendocrine domain have revealed promising avenues for developing targeted treatments that could overcome the limitations of current pharmacological approaches for pituitary disorders.

Fig. 6.

Research progress on DHCR24 in neurological disorders. This schematic summarizes current evidence regarding the roles of DHCR24 across a spectrum of neurological disorders other than AD, integrating both mechanistic studies and clinically observed correlations. Figure created with Powerpoint and BioRender. (ATXN2: ataxin 2, CSVD-CI: cerebral small vessel disease-related cognitive impairment, EAAT2: excitatory amino acid transporter 2, polyQ: polyglutamine, SCA2: spinocerebellar ataxia type 2, ST14A: striatum-derived cell line from embryonic day 14 rat, TREM2: triggering receptor expressed on myeloid cells 2)

The mechanistic underpinnings of DHCR24’s diverse functions involve complex interactions with multiple signaling pathways and cellular processes. Its regulation appears to be influenced by epigenetic modifications, nuclear receptor signaling, and sterol-responsive elements, creating a sophisticated control system that responds to both metabolic demands and stress conditions. Recent advances in understanding DHCR24’s allosteric regulation have enabled the development of specific inhibitors like U18666A, providing valuable tools for further investigating its biological functions and therapeutic applications.

Despite significant advances, critical knowledge gaps persist in our understanding of the comprehensive regulatory network governing DHCR24 expression and activity, its cell-type-specific roles within the nervous system, and its interplay with other metabolic pathways across various disease contexts. Moving forward, research should focus on elucidating these mechanisms through integrated multi-omics strategies, advanced animal models that more accurately recapitulate human disease characteristics, and rigorous validation in human tissues at different stages of pathology. Furthermore, translational studies aimed at exploring targeted DHCR24 modulation, such as small-molecule therapeutics and gene-based interventions, will be crucial to fully realizing its clinical potential.

In conclusion, DHCR24 represents a pivotal molecular node connecting cholesterol metabolism with fundamental processes in neurological health and disease. Its broad involvement across multiple disorders, combined with its dual role in metabolic regulation and neuroprotection, establishes DHCR24 as both a valuable biological marker and a highly promising therapeutic target. The continued investigation of this multifunctional enzyme will likely yield important insights into disease mechanisms and contribute to the development of innovative treatment strategies for various neurological and neuroendocrine conditions.

Conclusion and future direction

Based on the comprehensive review of current evidence, DHCR24 emerges as a multifunctional enzyme with critical importance in both physiological and pathological processes. Its fundamental role in cholesterol biosynthesis, which is complemented by its extensive neuroprotective properties that include the mitigation of Aβ toxicity, oxidative stress, and apoptotic pathways, establishes DHCR24 as a key regulator of cellular homeostasis. The enzyme’s involvement in hormone-mediated neuroprotection, particularly through estrogen and thyroid hormone signaling pathways, further extends its functional significance in central nervous system development and maintenance. Additionally, DHCR24 demonstrates metabolic responsiveness to insulin-like growth factor 1 and glucose fluctuations, highlighting its relevance in diabetic neuropathy, while its recently discovered anti-inflammatory functions through the rHDL/ApoA-I pathway suggest broader therapeutic applications. Despite these advances, several aspects of DHCR24 biology warrant further investigation, including its precise regulatory mechanisms, cell-type-specific functions within the nervous system, and potential as a therapeutic target across various neurological and metabolic disorders. Future research should focus on elucidating these mechanisms and exploring translational applications to fully realize the clinical potential of this remarkably versatile enzyme.

DHCR24 exhibits a sophisticated multi-layered regulatory system that integrates structural, transcriptional, and pharmacological dimensions. The enzyme’s functionally folded conformation adopts a distinctive endoplasmic reticulum membrane topology with spatially separated functional domains that establish its fundamental catalytic framework. Genomic investigations have revealed an elaborate transcriptional control architecture featuring nuclear hormone receptor binding motifs, specialized response elements for lipid-sensing receptors, and dynamic epigenetic modifications that collectively enable precise metabolic adaptation. The identification of the SRE provides a crucial feedback mechanism that directly couples DHCR24 expression to cellular cholesterol demands. These comprehensive regulatory features underscore DHCR24’s pivotal position at the intersection of cholesterol homeostasis and broader cellular metabolic networks, highlighting its importance as both a metabolic regulator and a potential therapeutic target in cholesterol-related disorders.

Research in the new century has collectively confirmed and deepened DHCR24 as a pivotal regulatory factor in cholesterol biosynthesis, with functions extending far beyond its role as a terminal enzyme in this pathway. Its activity is precisely regulated at multiple levels, including transcriptional control through SREBP-responsive elements and post-translational mechanisms such as phosphorylation, which together enable cells to finely tune the homeostasis of cholesterol and desmosterol. The functional significance of DHCR24 profoundly influences human pathophysiology; its deficiency disrupts membrane lipid raft integrity, promotes the amyloidogenic processing of APP and Aβ production, thereby providing a direct mechanistic explanation for AD. Furthermore, inhibiting DHCR24 has emerged as a powerful metabolic reprogramming strategy, capable of triggering endogenous PUFA biosynthesis, generating pro-lipolytic lipids, and modulating immunoinflammatory responses. This fundamental understanding has now been successfully translated into a promising therapeutic paradigm, paving the way for developing novel, resource-efficient lipid-lowering and neuroprotective strategies. Consequently, DHCR24 serves as a core therapeutic target, and its modulation enables precise control over cholesterol biosynthetic flux, holding broad implications for treating metabolic and neurodegenerative disorders.

Taken together, the evidence accumulated to date underscores the pivotal role of DHCR24 as both a terminal enzyme in cholesterol biosynthesis and a multifunctional regulator of neuronal integrity, placing it at the central node of lipid metabolism and neurological disease pathogenesis. Beyond its classical role in catalyzing the conversion of desmosterol to cholesterol and thereby sustaining lipid homeostasis, DHCR24 has been increasingly recognized for its antioxidant properties and its ability to counteract apoptosis. DHCR24 has emerged as a critical regulator of cholesterol metabolism in the central nervous system, with profound implications for the pathogenesis and potential treatment of neurodegenerative diseases. Beyond its canonical enzymatic role in catalyzing the conversion of desmosterol to cholesterol, DHCR24 contributes to the maintenance of neuronal membrane integrity, synaptic function, and intracellular signaling cascades, thereby safeguarding neural homeostasis. Increasing evidence indicates that DHCR24 resides at the crucial interface between lipid metabolism and neurodegeneration, functioning as a molecular bridge that links metabolic dysregulation with proteinopathy. In particular, its capacity to modulate tauopathy, Aβ pathology, and associated synaptic deficits highlights its potential as a promising therapeutic target. Thus, the upregulation of DHCR24 expression or activity may represent a viable strategy for counteracting multiple pathological processes that underlie cognitive decline. To date, research on DHCR24 has been predominantly focused on basic science, with relatively few population-based studies undertaken from a clinical epidemiological perspective. Although existing studies have confirmed that DHCR24 is involved in estrogen-dependent regulation, the limited number of existing human studies has neither examined its association with sex nor employed sufficiently large sample sizes. Nevertheless, among the 12 cases of Desmosterolosis reported to date, a slight female predominance is observed, with a female-to-male ratio of 7:5. Given the well-established link between estrogen and sex, we infer that DHCR24 may play an important role in sex-dependent diseases. Hence, to fully exploit its translational potential, further investigations are required to delineate its cell–type–specific functions, clarify its interactions with diverse signaling pathways, and evaluate therapeutic interventions aimed at restoring DHCR24 function in the context of complex human neurological disorders. Future investigations aimed at elucidating the precise molecular mechanisms through which DHCR24 integrates lipid metabolism with cellular stress-response pathways, as well as the development of therapeutic strategies designed to restore or augment its activity, may open promising avenues for the prevention and treatment of AD, ischemic stroke, and inherited disorders such as Desmosterolosis, all of which share a common pathogenic substrate of cholesterol dysregulation and compromised neuronal resilience.

Abbreviations

AAV

Adeno-associated Virus

Aβ

Amyloid β-Peptide

Abca1

ATP-binding Cassette Transporter A1

Abcg1

ATP-binding Cassette Transporter G1

AD

Alzheimer's Disease

Akt

Protein Kinase B

ApoA-I

Apolipoprotein A-I

ApoE4

Apolipoprotein E4

APP

Amyloid Precursor Protein

ARE

Androgen Response Element

ATXN2

Ataxin 2

BACE1

β-secretase 1

BBB

Blood–brain barrier

BDNF

Brain-derived Neurotrophic Factor

CAG

Cytosine-adenine-guanine

CaMK-Ⅱ

Calmodulin-dependent Protein Kinase 2

CAR/RXR

Constitutive Androstane Receptor/Retinoid X Receptor

CNS

Central Nervous System

CpG

Cytosine-phosphate-Guanine

CPT1A

Carnitine Palmitoyltransferase 1A

CSVD

Cerebral Small Vessel Disease

CSVD-CI

Cerebral Small Vessel Disease-related Cognitive Impairment

CYP46A1

Cytochrome P450 family 46 subfamily A member 1

DHCR24

3β-hydroxysterol 24-reductase

DR4

Direct Repeat 4

DHCR7

7-Dehydrocholesterol Reductase

DNA

Deoxyribonucleic Acid

DPI

Days post-injury

EAAT2

Excitatory Amino Acid Transporter 2

EAE

Experimental Autoimmune Encephalomyelitis

EBP

Emopamil Binding Protein

ERK

Extracellular Signal-regulated Kinase

EWAS

Epigenome-wide Association Study

EZH2

Enhancer of Zeste Homologue 2

FAD

Flavin Adenine Dinucleotide

FHS

Framingham Heart Study

FNC

Fetal Neuroepithelial Cells

GGA3

Golgi-localized γ-ear-containing ADP-ribosylation factor-binding Protein

GH

Growth Hormone

GL

Granulosa-lutein

GSK3β

Glycogen Synthase Kinase 3β

H3K27me3

Histone H3 lysine 27 trimethylation

HD

Huntington’s Disease

HDAC

Histone Deacetylase

HDL-C

High-density Lipoprotein Cholesterol

Hes1

Hes Family bHLH Transcription Factor 1

HMGCR

3-hydroxy-3-methylglutaryl-coenzyme A reductase

HNRNPK

Heterogeneous Nuclear Ribonucleoprotein K

HOMA-IR

Homeostatic Model assessment for Insulin Resistance

HTT

Huntingtin Protein

IFN-β

Interferon-beta

IGF-1

Insulin-like Growth Factor 1

IR

Insulin Resistance

KD

Ketogenic Diet

LDL-C

Low-density Lipoprotein Cholesterol

LDLR

Low-Density Lipoprotein Receptor

LXR

Liver X Receptor

MCAO

Middle Cerebral Artery Occlusion

MEK

Mitogen-activated Protein Kinase Kinase

mRNA

Messenger Ribonucleic Acid

mTOR

Mechanistic Target of Rapamycin

mHTT

Mutant HTT

NADPH

Nicotinamide Adenine Dinucleotide Phosphate (reduced form)

NF-Y

Nuclear Factor-Y

Notch1

Notch Receptor 1

NPS

Neuropsychiatric Syndrome

NVU

Neurovascular unit

OA-NO₂

Nitro-oleic acid

PCs

Phosphatidylcholines

PI3-K

Phosphatidylinositol 3-Kinase

PolyQ

Polyglutamine

PP2A

Protein Phosphatase 2A

PPARγ

Peroxisome Proliferator-activated Receptor γ

PS1

Presenilin 1

PSD95

Postsynaptic Density Protein 95

PUFA

Polyunsaturated Fatty Acid

PXR/RXR

Pregnane X Receptor/Retinoid X Receptor

Ras

Rat Sarcoma Viral Oncogene Homolog

rHDL

Reconstituted High-density Lipoprotein

RIPK1

Receptor-interacting Serine/Threonine-protein Kinase 1

RNA-seq

RNA-sequencing

ROS

Reactive Oxygen Species

SCA2

Spinocerebellar Ataxia Type 2

SCI

Spinal Cord Injury

SD

Sprague-Dawley

Seladin-1

Selective Alzheimer’s Disease Indicator-1

SERMs

Selective Estrogen Receptor Modulators

Sp1

Specificity Protein 1

SIRT6

Sirtuin 6

siRNA

Small Interfering RNA

SRE

Sterol Regulatory Element

SREBP

Sterol Regulatory Element-Binding Protein

TATA

Thymine-Adenine-Thymine-Adenine

Tau

Microtubule-associated Protein Tau

TDP43

TAR DNA-binding Protein 43

TGF-β

Transforming Growth Factor-β

The KR Pathway

The Kandutsch-Russell Pathway

TLR7

Toll-like Receptor 7

TMCAO

Transient Middle Cerebral Artery Occlusion

TMD

Transmembrane Domain

TREM2

Triggering Receptor Expressed on Myeloid Cells 2

WGCNA

Weighted Gene Co-expression Network Analysis

3’UTR

3’ untranslated region

17β-E2

17β-estradiol

24S-OHC

24(S)-hydroxycholesterol

Authors’ contributions

HZ and SL conducted the literature search, performed data analysis, and wrote the manuscript. YY contributed to the literature search. SQ contributed to language proofreading. TX obtained the funding, designed and critically revised the manuscript. YG contributed to the revision of the manuscript. All authors approved the final version of the manuscript.

Funding

Social Development Project Fund of Yangzhou City, NO. YZ2023067 (to YG), This work was supported by the China Postdoctoral Science Foundation, No. 2022M712689 (to TX). The Jiangsu Provincial Science and Technology Talent Project, No. FZ20240964 (to TX).

Data availability

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Declarations

Ethics approval and consent to participate

Not Applicable.

Competing interests

The authors declare no competing interests.