Is oxysterol accumulation a central physiological trigger of inflammaging?

Ageing is accompanied by a progressive disruption of lipid homoeostasis characterized by a declining cholesterol‐to‐oxysterol ratio. Oxidative stress–driven accumulation of bioactive oxysterols, particularly 7‐ketocholesterol (7‐KC), emerges as a central driver of cellular dysfunction during ageing. Age‐associated impairment of cytochrome P450–mediated detoxification and ATP‐binding cassette transporter dependent sterol efflux promotes oxysterol retention, triggering endoplasmic reticulum stress, mitochondrial failure, inflammasome activation and senescence‐associated secretory phenotypes. These events converge on chronic sterile inflammation, or inflammaging, linking lipid oxidation to atherosclerosis, neurodegeneration and tissue degeneration. Oxysterols thus function as integrative molecular nodes connecting redox imbalance to systemic ageing physiology.

Oxidative lipid remodelling and oxysterol accumulation in ageing

Ageing involves the progressive decline in physiological functions, marked by metabolic disruptions like shifts in the lipidome, where the cholesterol to oxysterol ratio decreases, promoting pathology (Ashique et al., 2026). Oxidative stress causes oxysterols, which are products of oxidized cholesterol, to build up and disturb cellular equilibrium. In addition to biosynthesis oxysterol clearance plays a critical role in maintaining sterol homoeostasis. Oxysterols are eliminated via hepatic conversion to bile acids, sulfation by SULT enzymes and efflux through ABC transporters. Ageing impairs these clearance pathways through reduced hepatic function, transporter downregulation and diminished enzymatic detoxification, thereby exacerbating systemic oxysterol accumulation and prolonging their pro‐inflammatory effects (de Medina, Silvente‐Poirot, & Poirot, 2022). In age‐related diseases such as atherosclerosis, Alzheimer's disease and macular degeneration this changed ratio causes inflammation, mitochondrial malfunction and cell death (Kakkar et al., 2025; Kakkar, Singh, Jasoria, et al., 2026; Kakkar, Singh, Singh, et al., 2026). In addition to keeping membranes fluid cholesterol is a precursor of bile acids and hormones. Autoxidation or enzymatic conversion to bioactive oxysterols such as 7‐ketocholesterol (7‐KC) is made possible by its Δ5 double bond (S, 2026; Sukumaran & S, 2026; Vejux et al., 2025; Zarrouk et al., 2014). Oxysterols are enzymatically generated via cytochrome P450 (CYP) enzymes, such as CYP46A1, CYP27A1 and CYP7A1, acting as ligands for Liver X Receptor (LXR) to promote cholesterol efflux and Sterol Regulatory Element‐Binding Protein(SREBP) inhibition via Insight, thus maintaining lipid balance through reactive oxygen species (ROS) induced downregulation and transcriptional alterations; ageing reduces CYP activity and detoxification by enzymes such as CYP3A and CYP7. Increased ROS causes non‐enzymatic oxidation at the C5–C6 link of cholesterol, producing highly cytotoxic oxysterols, including 25‐hydroxycholesterol and 7‐KC. These derivatives trigger endoplasmic reticulum (ER) stress, NLRP3 inflammasome activation and senescence‐associated secretory phenotype (SASP), fuelling chronic low‐grade inflammation (‘inflammaging’) and degeneration in tissues like brain, vasculature and liver (Brown, Sharpe, & Rogers, 2021; Gargiulo, Gamba, Testa, Leonarduzzi, & Poli, 2016). The age‐related decline in ABCA1 and ABCG1 transporters impairs sterol efflux, leading to oxysterol build‐up in macrophages and endothelial cells, which promotes foam cell formation and vascular pathology. In addition to ROS reactive nitrogen species (RNS) and reactive sulphur species (RSS) play a complex role in oxysterol biology. Through nitrosative alterations and peroxynitrite production, nitric oxide (NO) controls oxysterol signalling and cholesterol oxidation via endothelial and inducible nitric oxide synthases (eNOS/iNOS). One important RSS, hydrogen sulphide (H2S), affects ABCA1‐mediated efflux and CYP enzyme activity to regulate cholesterol homoeostasis. Additionally oxysterols are positioned within a larger redox network that drives inflammation when redox enzymes such as myeloperoxidase integrate ROS–RNS–RSS crosstalk, enhancing lipid oxidation and inflammatory signalling (Brahmi et al., 2025; Wu, Hu, & Zhu, 2018). To facilitate reverse cholesterol transport (RCT) to the liver for excretion ABCA1 and ABCG1 mediate the ATP‐dependent export of cholesterol and oxysterols to apoA‐I and high‐density lipoprotein (HDL). These transporters are upregulated in young cells by LXR activation, which preserves lipid homoeostasis; however as cells age their expression is decreased due to ROS‐mediated damage and epigenetic silencing (Bazioti et al., 2022; Matsuo, 2022). Table 1 discusses the oxysterol‐mediated molecular mechanisms driving ageing and inflammaging.

Table 1.

Oxysterol‐mediated molecular mechanisms driving ageing and inflammaging

Oxysterol	Primary source	Key molecular targets/pathways	Cellular consequences	Age‐related pathologies
7‐KC	ROS‐mediated cholesterol oxidation	PERK–CHOP, NLRP3 inflammasome, lysosomal membranes, Bax/Bak	ER stress, mitochondrial dysfunction, oxiapoptophagy, pyroptosis	Atherosclerosis, Alzheimer's disease, AMD
25‐Hydroxycholesterol	Non‐enzymatic oxidation; immune activation	LXR, SREBP inhibition, NF‐κB	Inflammation, sterol efflux dysregulation	Inflammaging, neurodegeneration
27‐Hydroxycholesterol	CYP27A1‐mediated oxidation	LXR activation, mitochondrial stress	Altered lipid signalling, ROS amplification	Vascular ageing, metabolic dysfunction
24S‐Hydroxycholesterol	CYP46A1 (brain‐specific)	LXR, cholesterol clearance	Neurotoxicity at high levels	Alzheimer's disease
Mixed oxysterols	Ageing lipidome	ABCA1/ABCG1 suppression	Foam cell formation, endothelial dysfunction	Plaque instability, thrombosis

Note: Oxysterol accumulation reflects an age‐dependent imbalance between CYP‐mediated detoxification, oxidative generation and ABC transporter‐dependent efflux.

Abbreviations: AMD, age‐related macular degeneration; CYP, cytochrome P450; ER, endoplasmic reticulum; ROS, reactive oxygen species; LXR‐Liver X Receptor, SREBP‐Sterol Regulatory Element‐Binding Protein.

Oxysterol‐induced foam cell formation, endothelial dysfunction and oxiapoptophagy in ageing

In senescent macrophages diminished efflux causes intracellular lipid droplets rich in cytotoxic oxysterols such as 7‐KC, triggering ER stress, inflammasome activation and foam cell differentiation hallmarks of atherosclerosis and ‘inflammaging’. Endothelial dysfunction follows, with impaired barrier integrity and pro‐thrombotic shifts. In senescent macrophages impaired cholesterol efflux fosters lipid‐laden droplets rich in cytotoxic oxysterols such as 7‐KC, which provoke ER stress via PERK/CHOP activation, NLRP3 inflammasome signalling and foam cell differentiation central to atherosclerotic plaque instability and ‘inflammaging’. This macrophage pathology extends to adjacent endothelium, eliciting oxidative insult that erodes barrier function through ICAM‐1 overexpression and MAPK cascades, while instigating a pro‐thrombotic state marked by tissue factor (TF) induction and blunted vasodilatation (Gajendran, Ganamurali, & Sabarathinam, 2025). Oxiapoptophagy, a term coined by Nury et al. (2021), encapsulates the hybrid cell death modality triggered predominantly by 7‐KC, fusing oxidative stress (oxi‐), apoptotic signalling (apopto‐) and defective autophagy (‐phagy)(Nury et al., 2021).

7‐KC induced autophagy blockade and oxiapoptophagy

To prevent autophagosome lysosome fusion and produce undegraded payloads 7‐KC embeds into lysosomal membranes, neutralizing acid hydrolases (such as cathepsin D) and raising intralysosomal pH. By impairing mitophagy this autophagic blockade increases ROS and fuels peroxide‐mediated oxidation of lipids, proteins and mitochondrial DNA (mtDNA). It also triggers caspase‐independent apoptosis by MPT pore opening and Bax/Bak oligomerization. The ‘clogging’ precipitates mitochondrial hyperfusion, bioenergetic collapse (ΔΨm loss) and cytosolic translocation of lysosomal enzymes, culminating in hybrid oxiapoptophagy distinct from classical apoptosis or ferroptosis by its autophagy dependence. In ageing contexts this manifests in foam cells and neurons, linking to plaque rupture and neurodegeneration (Ghzaiel, Nury, Zarrouk, Vejux, & Lizard, 2022).

Oxysterols as endogenous DAMPs: NLRP3 inflammasome activation and inflammaging

As strong endogenous danger signals (DAMPs), oxysterols, especially 7‐KC, pharmacologically stimulate and activate the NLRP3 inflammasome in aged cells, increasing sterile inflammation. In LPS‐sensitized macrophages and retinal pigment epithelial (RPE) cells 7‐KC first upregulates NLRP3 and pro‐IL‐1β/IL‐18 via NF‐κB priming; subsequent lysosomal instability causes K⁺ efflux, ASC oligomerization and caspase‐1 autoactivation. This drives pyroptosis and SASP amplification, which are essential for ‘inflammaging’ in atherosclerosis, age‐related macular degeneration (AMD) and neurodegeneration. It also cleaves pro‐cytokines into mature interleukin 1β (IL‐1β) and IL‐18 (Indaram et al., 2015; Xiang Li et al., 2014; Martins, Ferreira, Palotás, Rocha, & Reis, 2023; Shi et al., 2015). Pro‐IL‐1β and pro‐IL‐18 are proteolytically cleaved by activated caspase‐1 into their physiologically active counterparts, IL‐1β and IL‐18, which are then released to increase systemic and paracrine inflammation. A hallmark of inflammasome activation, this cytokine maturation stage directly aids in the spread of SASP as people age (Barker, Taxman, & Ting, 2011; Xia Li et al., 2023).

Oxysterols as central integrators of ageing pathophysiology

Ageing is driven by progressive disruption of cholesterol homeostasis, marked by a shift towards oxysterol accumulation under oxidative stress. Declining CYP‐mediated detoxification and impaired ABCA1/ABCG1 efflux promote the retention of cytotoxic oxysterols, particularly 7‐KC, across ageing tissues. These lipotoxic metabolites induce ER stress, mitochondrial dysfunction, inflammasome activation and a hybrid cell death programme termed oxiapoptophagy, reinforcing cellular senescence and inflammaging. By acting as endogenous danger signals oxysterols integrate redox imbalance with chronic sterile inflammation and degenerative pathology. Targeting oxysterol generation, signalling or clearance represents a promising pharmacological strategy to mitigate age‐associated metabolic, vascular and neurodegenerative disorders. Therapeutically strategies to reduce oxysterol burden include the inhibition of cholesterol oxidation (e.g. antioxidants targeting lipid peroxidation), enhancement of sterol efflux via LXR agonists and promotion of enzymatic detoxification through CYP modulation. Emerging approaches also include nanoparticle‐based delivery systems and sulfation‐enhancing strategies to accelerate oxysterol clearance, representing promising interventions to attenuate inflammaging.

Conclusion

Oxysterols emerge as pivotal molecular intermediates in the physiology of ageing, translating oxidative stress into chronic inflammation, cellular senescence and tissue degeneration. Age‐related impairment of sterol detoxification and efflux transforms oxysterols from regulatory lipid mediators into cytotoxic drivers of oxiapoptophagy and inflammasome activation. By integrating redox imbalance, lipid signalling and innate immune activation oxysterols provide a unifying framework for understanding inflammaging and age‐associated diseases. Targeting oxysterol generation, trafficking or signalling may therefore represent a promising strategy to restore lipid homoeostasis and mitigate degenerative ageing phenotypes. This expanded redox‐centric framework positions oxysterols not merely as lipid by‐products but as dynamic integrators of ROS–RNS–RSS signalling networks in ageing biology.

Additional information

Competing interests

None.

Author contributions

N.G., S.S.: conceptualization, visualization, software, validation, writing – reviewing and editing. Both authors contributed equally.

Funding

No funding was received for this study

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