Lactylation and N6-Methyladenosine RNA modification in neuropsychiatric sequelae after intracerebral hemorrhage: a hypothesis-generating metabolic–glial–circuit framework

Abstract

Depression, anxiety, cognitive impairment, fatigue, and sleep disturbance are clinically important sequelae of intracerebral hemorrhage (ICH), but the molecular events linking acute hemorrhagic injury to delayed neuropsychiatric vulnerability remain incompletely defined. This narrative review synthesizes evidence identified through targeted PubMed/MEDLINE and Europe PMC searches updated through 31 August 2026, supplemented by citation chaining. Evidence was categorized as direct ICH evidence, supportive evidence from other stroke or central nervous system models, or hypothesis-generating evidence from other disease contexts. Acute hematoma-derived hemin, iron, thrombin, hypoxia, mitochondrial dysfunction, and altered glycolysis create a perihematomal metabolic–inflammatory environment characterized by oxidative stress and altered lactate handling. Direct preclinical ICH studies support site-specific H3K14la–PMCA2 and H3K18la–METTL3–LCN2 mechanisms, together with separate m6A-related pathways involving METTL3–TFRC, METTL3–YTHDF1–BCL-3, WTAP–UQCRQ, m6A-modified miR-873–RIPK3, and FTO–BCLW. These studies primarily address acute cell death, mitochondrial stress, and glial activation. Direct lactylation–m6A crosstalk evidence in ICH is currently limited to the H3K18la–METTL3–LCN2 axis, and no study has yet shown that this axis causes persistent depression, anxiety, cognitive impairment, or circuit dysfunction after ICH. We therefore present a hypothesis-generating metabolic–glial–circuit framework that separates demonstrated acute ICH mechanisms from proposed downstream neuropsychiatric links. Cell-specific, longitudinal, behavioral, circuit-level, and human validation is required before biomarker or therapeutic translation.

Introduction

Intracerebral hemorrhage (ICH) is among the most devastating stroke subtypes, defined by bleeding into the brain parenchyma after rupture of fragile cerebral vessels. Although ICH represents only a minority of all strokes, it causes disproportionate mortality, disability, and long-term health-care burden; recent therapeutic reviews also emphasize the lack of broadly effective disease-modifying treatments [1–3]. The early injury phase is driven by hematoma expansion, mass effect, increased intracranial pressure, perihematomal edema, and mechanical disruption of surrounding tissue. Secondary injury then evolves through oxidative stress, blood-brain barrier (BBB) disruption, neuroinflammation, mitochondrial dysfunction, and regulated cell-death pathways. In this context, recent evidence that methyltransferase-like 3 (METTL3) silencing attenuates ferroptosis by regulating transferrin receptor (TFRC) expression further supports ferroptosis as a relevant downstream mechanism in ICH progression [4]. Despite advances in neurosurgical management and neurocritical care, many survivors remain at high risk of persistent neurological and neuropsychiatric disability.

Beyond focal neurological deficits, ICH survivors may develop depression, anxiety, apathy, cognitive impairment, fatigue, and sleep disturbance. These outcomes are increasingly recognized as clinically meaningful, although the strength of evidence varies across symptom domains and some data still derive from broader post-stroke cohorts [5, 6]. The rationale for examining lactylation and m6A is not that either modification has already been shown to cause these syndromes. Rather, ICH creates a hemorrhage-specific substrate—hematoma toxicity, hemin and iron exposure, thrombin activation, intense glial reactivity, and disruption of fronto-striato-thalamic and limbic networks—in which metabolic and RNA-regulatory injury pathways could plausibly influence longer-term recovery [7, 8]. Most relevant mechanistic studies, however, terminate during the acute or subacute injury phase and measure ferroptosis, edema, inflammatory activation, or neurological deficit scores rather than depression-like behavior, cognition, sleep, synaptic physiology, or circuit connectivity. Accordingly, this review separates mechanisms demonstrated in ICH from their hypothesized extension to post-ICH neuropsychiatric dysfunction.

Recent ICH-focused and broader metabolic-epigenetic studies suggest that metabolic reprogramming may help connect acute hemorrhagic injury with delayed glial and neuronal vulnerability [9–11]. In the perihematomal region, local hypoperfusion, mitochondrial injury, inflammatory-cell recruitment, and impaired substrate utilization can increase glycolytic stress and lactate accumulation. Lactate is no longer viewed only as a metabolic end-product; it can also function as a signaling metabolite that influences histone and non-histone lactylation, thereby shaping transcriptional programs related to inflammation, cell survival, and plasticity in a context-dependent manner. In parallel, N6-methyladenosine (m6A) RNA methylation regulates RNA splicing, stability, translation, and stress responses through methyltransferases, demethylases, and reader proteins. In ICH, METTL3-dependent regulation of TFRC and METTL3/YTHDF1-dependent regulation of BCL-3 provide specific examples linking m6A machinery to ferroptosis-related injury [4, 12]. Although studies in other disease contexts suggest potential crosstalk between lactylation and m6A methylation, this interaction should be framed in ICH as an emerging and testable mechanism rather than an established causal pathway.

Glial cells, particularly astrocytes and microglia, are central to the brain response after hemorrhagic injury. They contribute to hematoma containment and debris clearance, but prolonged or maladaptive activation can amplify cytokine release, complement signaling, BBB dysfunction, excitotoxicity, and synaptic vulnerability. Rather than treating “A1 astrocytes” as a fixed cell identity, it is more accurate to describe A1-like neurotoxic reactive astrocyte programs that may emerge under specific injury conditions. Notably, histone H3 lysine 18 lactylation (H3K18la) has been associated with METTL3-dependent m6A modification of lipocalin 2 (LCN2), promoting A1-like astrocyte activation and aggravating brain injury after ICH [9]. This finding provides one of the clearest mechanistic links between metabolic alteration, histone lactylation, m6A RNA methylation, and glial neurotoxicity in hemorrhagic brain injury, although its direct relevance to human post-ICH depression still requires behavioral and clinical validation.

Given the multifactorial nature of ICH pathology, this review examines lactylation and m6A RNA methylation as two potentially intersecting regulatory layers, not as broadly established interconnected systems. Direct ICH evidence currently supports one specific crosstalk example: H3K18la-associated, METTL3-dependent m6A regulation of LCN2 in reactive astrocytes [9]. The H3K14la–PMCA2 pathway and other m6A axes are better interpreted as separate acute ICH injury modules involving calcium dysregulation, ferroptosis, necroptosis, mitochondrial stress, or inflammation [4, 10, 12]. Connections from these molecular events to mood- and cognition-related circuits are inferred from clinical-anatomical studies and broader central nervous system literature. We therefore use an evidence-graded framework with three explicit levels: demonstrated ICH molecular or cellular mechanisms, supportive evidence from adjacent CNS settings, and hypothesis-generating links to persistent neuropsychiatric outcomes. This constrained conceptual model is summarized in Fig. 1.

Fig. 1.

Three-stage conceptual schematic showing progression from acute intracerebral hemorrhage to molecular and cellular injury and then hypothesized circuit and behavioral vulnerability. Hematoma-related metabolic–inflammatory stress feeds into site-specific histone lactylation and separate stress-responsive m6A pathways, which are linked to neuronal ferroptosis, astrocyte reactivity, mitochondrial stress, and cell death. Their extension to synaptic failure, network disconnection, depression, cognitive impairment, anxiety, and related symptoms is hypothesis-generating rather than established

Literature search and evidence appraisal

For this revision, targeted searches were conducted in PubMed/MEDLINE and Europe PMC from database inception through 31 August 2026, supplemented by backward citation chasing from included reviews and primary studies and forward checks of publisher and DOI records. Search combinations included (“intracerebral hemorrhage” OR ICH OR “hemorrhagic stroke”) AND (depression OR anxiety OR apathy OR “cognitive impairment” OR fatigue OR sleep), together with terms for lactate, lactylation, H3K14la, H3K18la, m6A, METTL3, FTO, ALKBH5, WTAP, YTHDF1, LCN2, ferroptosis, necroptosis, astrocyte, microglia, synapse, electrophysiology, LTP, and neural circuit. Peer-reviewed human ICH cohorts and experimental ICH studies were prioritized. Reviews were used to establish context and identify primary reports; non-ICH studies were retained only when they informed biological plausibility. Because this was a targeted narrative review, no PRISMA flow diagram, formal risk-of-bias meta-analysis, or quantitative evidence pooling was undertaken.

For synthesis, “direct ICH evidence” required a human ICH cohort or an ICH animal or cell model that directly measured the named mechanism or outcome. “Supportive evidence” comprised studies from other stroke or CNS injury models, or ICH studies that addressed an adjacent injury endpoint without a neuropsychiatric or circuit readout. “Hypothesis-generating evidence” comprised non-ICH disease contexts or mechanistic inferences linking separate findings. A molecular result was not treated as evidence for a post-ICH psychiatric outcome unless the same study included a relevant behavioral, circuit, or human association endpoint. This hierarchy was applied throughout the Abstract, figure legend, mechanistic sections, tables, Discussion, and Conclusion.

Neuropsychiatric burden after intracerebral hemorrhage

Prevalence and clinical spectrum of post-ICH psychiatric disorders

ICH-specific estimates vary substantially with case definition, assessment method, disease severity, and survivorship. In a cohort of young ICH survivors assessed at a median of 9.7 years after the event, depressive symptoms were present in 23.1% (30/130) and anxiety in 40.0% (52/130) [13]. In a multicenter electronic health-record cohort, depressive diagnostic codes were recorded in 3.8% (132/3422) by 3 months, whereas active PROMIS screening at 1, 3, and 12 months identified depressive symptoms in 22.4% (26/116); screening was substantially more likely than coded diagnosis to identify symptoms (OR 7.20, 95% CI 4.5–11.5, P < 0.0001) [14]. Among MISTIE III survivors with large spontaneous ICH, 36% (111/308) met the CES-D depression threshold at day 180; unchanged or worsening modified Rankin Scale status from day 30 to day 180 was more frequent in participants with depression than in those without depression (42.3% vs. 25.9%, P = 0.004) [15]. These estimates should not be pooled directly because the cohorts, screening instruments, and survival filters differ.

Long-term anxiety also remains common. In the prospective PITCH cohort, anxiety was present in 17% (95% CI 12–23) at 1–2 years, 27% (95% CI 19–34) at 3–5 years, and 21% (95% CI 12–30) at 6–8 years after ICH; among participants with anxiety, co-occurring depressive symptoms were reported in 48%, 61%, and 56% at the respective time points [16]. A 2026 clinic-based cohort assessed at a median of 5.7 years after spontaneous ICH found affective symptoms in 37.9% and apathy/vegetative symptoms in 32.6%; deep cerebral microbleed burden was independently associated with affective symptoms (adjusted OR 1.215, 95% CI 1.03–1.43, P = 0.021), with cognitive impairment mediating 35.9% of the association (indirect-effect P = 0.012) [17]. These Neuropsychiatric Inventory–Questionnaire subsyndromes are broader than a diagnosis of depression or anxiety and should not be interpreted as equivalent prevalence measures. Comparative acute stroke data also suggest a substantial depressive burden after hemorrhagic stroke [18], but instrument and timing differences remain important.

Cognitive dysfunction is another disabling and time-dependent sequela of ICH. A systematic review and meta-analysis of 18 studies (3270 patients) estimated a pooled prevalence of 46% (95% CI 35.9–55.9) across follow-up from 8 days to 4 years; pooled estimates were 55% within 6 months and 35% from more than 6 months to 4 years, although cognitive instruments and domains varied widely [19]. The American Heart Association/American Stroke Association scientific statement similarly emphasizes heterogeneity in timing, phenotype, and assessment after hemorrhagic stroke [20]. Cognitive deficits often involve executive function, attention, processing speed, and memory and are associated with psychiatric outcomes and functional status [21]. Broader stroke literature suggests that hypothalamic–pituitary–adrenal axis dysregulation may contribute to cognitive and emotional vulnerability, but this mechanism remains insufficiently validated in ICH-specific cohorts [22]. White matter hyperintensity burden and prior hemorrhagic injury may also indicate small-vessel disease and reduced brain reserve that modify recurrent stroke risk and cognitive recovery [23].

Sleep disturbance is clinically relevant after stroke and may also contribute to the post-ICH neuropsychiatric phenotype. Insomnia, excessive daytime sleepiness, fatigue, and disrupted sleep-wake regulation can aggravate mood symptoms, impair attention, and limit cognitive restoration. In ICH, these disturbances may arise from injury to sleep-regulating networks, neuroinflammatory signaling, metabolic stress, medication effects, and reduced daytime activity. Current evidence linking fatigue, sleep disturbance, and depression is supported mainly by broader post-stroke data, but it highlights a plausible interaction between systemic inflammation, sleep regulation, and neuropsychiatric outcomes [24]. These observations support routine screening for sleep and fatigue symptoms in ICH survivors, while also underscoring the need for ICH-specific longitudinal studies. In summary, post-ICH psychiatric disorders should be regarded as a multidimensional syndrome rather than an isolated depressive reaction to disability. Depression is central to this syndrome, but anxiety, apathy, PTSD symptoms, cognitive impairment, fatigue, and sleep disturbance often coexist and may reinforce one another. These complications can impair functional recovery and quality of life, yet their biological mechanisms remain incompletely defined. Future studies should clarify how hemorrhage-specific metabolic stress, glial reactivity, synaptic dysfunction, and epigenetic mechanisms, including lactylation and m6A RNA methylation, contribute to persistent mood and cognitive symptoms after ICH.

Impact on recovery, quality of life, and long-term prognosis

Neuropsychiatric complications after ICH, particularly depression and cognitive impairment, may influence recovery beyond the effects of motor deficits alone and are closely related to patients’ quality of life [25]. Depressive symptoms can reduce motivation and adherence to rehabilitation, whereas cognitive impairment can limit learning, compensatory strategy use, and self-management; early cognitive impairment may also affect subsequent functional recovery trajectories after ICH [26]. Fatigue and sleep disturbance may further weaken functional gains and increase dependence. Psychological outcomes after hemorrhagic stroke are closely linked to functional status and should therefore be incorporated into long-term recovery assessment [27]. Although broader stroke studies consistently associate post-stroke depression with poorer rehabilitation outcomes and functional recovery, ICH-specific evidence should be interpreted alongside lesion location, hematoma severity, small-vessel disease burden, medical comorbidities, and baseline functional status [28]. Under-recognition remains common because psychiatric, cognitive, and sleep-related symptoms may be overshadowed by acute neurological deficits. A clearer understanding of the biological links among hemorrhagic injury, metabolic stress, glial activation, and circuit dysfunction is therefore essential for developing biomarkers and mechanism-based interventions that improve long-term recovery and quality of life in ICH survivors.

Why post-ICH depression may be biologically distinct from general post-stroke depression

Unique pathophysiological features of ICH: hematoma, hemin, iron overload, and thrombin

ICH initiates a pathophysiological cascade that differs from ischemic stroke because the hematoma produces both mechanical tissue disruption and sustained exposure to toxic blood-derived products. Erythrocyte lysis releases hemoglobin, hemin, and iron, which promote oxidative stress, mitochondrial injury, lipid peroxidation, and ferroptosis. Although ferroptosis is not unique to ICH, the local concentration and persistence of blood-derived iron make iron-mediated oxidative injury particularly prominent after hemorrhage, supporting the rationale for iron-handling and anti-ferroptotic strategies [29–31]. Thrombin is another defining component of the hemorrhagic microenvironment. Beyond its role in hemostasis, excessive thrombin can activate protease-activated receptor-1 (PAR-1) on microglia, astrocytes, endothelial cells, and neurons, thereby promoting inflammatory signaling, BBB disruption, leukocyte recruitment, edema formation, and secondary injury [32, 33]. Elevated thrombin-antithrombin (TAT) complex levels in hematoma fluid and plasma are associated with ICH severity, indicating persistent coagulation activity within the lesion environment. Experimental studies further suggest that thrombin can induce autophagy in perihematomal neurons and astrocytes; this response may be adaptive at moderate levels but harmful when excessive or sustained [34, 35].

The hematoma also releases damage-associated molecular patterns, including high-mobility group box 1 (HMGB1), that amplify innate immune activation. HMGB1 released from injured or necrotic cells can promote microglial activation, inflammatory cytokine production, BBB injury, and edema. In experimental ICH, the HMGB1 inhibitor glycyrrhizin attenuated brain injury, supporting HMGB1 as a relevant link between coagulation-related injury and innate immune signaling [36]. Iron overload following erythrocyte lysis is particularly important because it connects hematoma degradation to mitochondrial dysfunction and ferroptosis. Free iron catalyzes reactive oxygen species generation through Fenton chemistry, damages mitochondrial membranes, and increases neuronal and glial susceptibility to lipid peroxidation. Iron chelation and other neuroprotective approaches have shown benefits in preclinical models, although clinical translation remains challenging [30, 31]. Lactoferrin, an iron-binding glycoprotein delivered in part by infiltrating neutrophils, may facilitate hematoma detoxification and resolution by supporting iron handling, erythrophagocytosis, and efferocytosis through microglia/macrophages [37].

The perihematomal immune microenvironment is shaped by these blood-derived signals. Thrombin- and hemin-associated stress can promote pro-inflammatory microglial programs, whereas repair-associated microglia/macrophages support hematoma clearance and tissue remodeling. Experimental work indicates that neutrophil-microglia interactions, monocyte-derived macrophages, and microglial activation states all contribute to the balance between injury amplification and hematoma resolution [38, 39]. Complement signaling adds another layer of complexity: complement component C1q participates in inflammatory responses and hematoma-related injury, but its role may vary depending on timing, cell type, and clearance requirements [40, 41]. These studies support the broader principle that early coagulation biology influences hematoma evolution, but they should not be interpreted as direct evidence for post-ICH depression. In summary, post-ICH depression should not be viewed as a simple extension of general PSD. Hematoma mass effect, hemin and iron toxicity, thrombin signaling, complement activation, BBB disruption, edema, and immune-cell recruitment create a hemorrhage-specific biological environment. These mechanisms provide the tissue context in which metabolic stress, glial reactivity, lactylation, and m6A RNA methylation may later influence synaptic and circuit vulnerability.

Intense glial reactivity and distinct neuroinflammatory signatures

Following ICH, astrocytes and microglia display strong but heterogeneous reactive programs that shape neuroinflammation, hematoma clearance, BBB integrity, metabolic support, and synaptic vulnerability. The older A1/A2 and M1/M2 terminology remains useful as shorthand, but it should not be treated as a fixed binary classification. After ICH, glial states are likely to be time-, region-, and stimulus-dependent, with injury-promoting and repair-supporting programs often coexisting within the perihematomal region. A1-like neurotoxic astrocyte programs are typically associated with complement-related and inflammatory modules, including C3 and interleukin-1 family signaling [42, 43]. Activated microglia can induce neurotoxic reactive astrocytes through cytokine combinations such as IL-1α, TNF-α, and C1q, providing a mechanistic basis for microglia-astrocyte inflammatory crosstalk [44]. In hemorrhagic injury, blood-derived products such as bilirubin and hemin may further bias astrocytes toward inflammatory and neurotoxic states, although these phenotypes should be described as A1-like programs rather than stable astrocyte identities [45].

Microglia and monocyte-derived macrophages rapidly acquire phagocytic functions after ICH and are essential for hematoma debris clearance. However, excessive or prolonged activation is accompanied by secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), leukotrienes, and other mediators that can aggravate BBB injury, edema, oxidative stress, and neuronal dysfunction [38, 39]. Complement activation, particularly C1q-related signaling, may further modulate neutrophil infiltration, microglial activation, synaptic vulnerability, and tissue injury [40]. Therefore, post-ICH depression should be linked to maladaptive and unresolved glial reactivity without ignoring the essential reparative role of glia in hematoma resolution. Compared with ischemic stroke, ICH produces a distinct neuroinflammatory milieu because the initiating triggers are blood-derived toxins, coagulation products, iron overload, and hematoma clearance demands. This distinction supports the need for therapeutic strategies that modulate harmful glial programs while preserving phagocytosis, iron handling, metabolic buffering, and tissue repair.

Spatial overlap between lesion site and mood-regulating circuits

ICH frequently affects the basal ganglia, thalamus, lobar cortex, and subcortical white matter, regions that overlap with fronto-striato-thalamic and limbic networks involved in motivation, reward processing, emotional regulation, memory, and executive control. Hematoma formation, edema, and secondary inflammation in these regions can disrupt communication among the prefrontal cortex, striatum, thalamus, hippocampus, and amygdala, thereby providing an anatomical substrate for depression, anxiety, apathy, and cognitive impairment after hemorrhagic stroke [46]. Neuroimaging studies support the concept that basal ganglia-thalamic hemorrhage can produce network-wide structural alterations and cognitive vulnerability. Damage to white matter tracts and thalamo-cortical or fronto-striatal connections may impair executive control, emotional salience processing, reward learning, and stress regulation [46, 47]. Nevertheless, lesion location should not be interpreted in isolation. Hematoma volume, perihematomal edema, white matter disease, premorbid psychiatric vulnerability, systemic complications, and rehabilitation context all influence whether a patient develops post-ICH depressive or anxiety symptoms.

The circuit basis of post-ICH depression may therefore be more anatomically constrained than primary depressive disorders, but it remains multifactorial. Clinical comparisons across stroke subtypes and ICH-specific data on depression severity support this multifactorial interpretation [18, 48]. This spatial overlap provides a framework for understanding how hemorrhage-induced metabolic stress and epigenetic mechanisms may influence mood-related outcomes. Lactylation may alter transcriptional programs in neurons and glia exposed to elevated lactate, while m6A RNA methylation may regulate transcript stability and translation of genes involved in inflammation, ferroptosis, synaptic remodeling, and neurotrophic signaling [4, 49]. In summary, the convergence between common ICH lesion sites and mood-regulating circuits suggests that post-ICH depression may emerge from both lesion-network disconnection and molecular remodeling within vulnerable circuits. Lactylation and m6A RNA methylation should therefore be framed as candidate mechanisms linking hemorrhagic metabolic stress to glial inflammation, synaptic plasticity failure, and neuropsychiatric dysfunction, rather than as established causal pathways for human post-ICH depression.

Metabolic stress after ICH: lactate accumulation as a signaling event

Local hypoxia and enhanced glycolytic flux in the perihematomal region

ICH disrupts local perfusion through hematoma mass effect, edema, vascular compression, and microvascular dysfunction. Together, these events create a perihematomal metabolic crisis in which oxygen delivery, substrate utilization, inflammatory signaling, edema formation, and mitochondrial function are simultaneously disturbed [50, 51]. Perfusion imaging studies support reduced perihematomal blood flow and altered perihematomal cerebral blood volume after ICH, and experimental work also indicates disturbed glucose metabolism in the acute perihematomal region [52, 53]. Under these conditions, affected cells may shift from oxidative phosphorylation toward glycolysis to maintain ATP production, but this response should be interpreted as a hypoxia- and inflammation-driven adaptation rather than a classical tumor-like Warburg program. Human ICH transcriptomic data further show staged myeloid activation in the living brain, with enrichment of hypoxia-inducible factor (HIF)-related and glycolytic programs during hematoma response and resolution [54]. Cerebral microdialysis studies provide broader support for lactate/pyruvate-based monitoring of metabolic crisis in acute brain injury, including ICH where available, but they do not define the cell-type origin of lactate in post-ICH neuropsychiatric outcomes [55, 56]. Thus, current evidence supports disturbed perihematomal perfusion and metabolism after ICH, whereas the magnitude, timing, and cellular sources of lactate accumulation remain incompletely defined. Glycolysis-associated metabolic remodeling is not restricted to neurons. Reactive astrocytes, microglia, monocyte-derived macrophages, neutrophils, and endothelial cells may all contribute to the perihematomal metabolic state. In the hypoxic, iron-rich, and inflammatory hematoma environment, HIF signaling can support glycolytic enzyme expression and provide metabolic flexibility for glia and infiltrating immune cells, allowing them to survive and function during hematoma response and resolution.

Perihematomal hypoxia and metabolic remodeling are closely linked to secondary injury. Edema formation, oxidative stress, BBB dysfunction, and inflammatory amplification can reinforce one another after ICH [51, 57, 58]. Lactate and related glycolytic intermediates may participate in this process by reflecting metabolic failure, local acidosis, and inflammatory-cell activity, but direct causality between lactate accumulation and post-ICH behavioral symptoms remains to be established. Experimental ICH studies further implicate PKM2-dependent glial metabolic activation and SPI1/PI3K/AKT/mTOR signaling in coupling metabolic remodeling to neuroinflammation [59, 60]. Clinically, reduced cerebral blood flow (CBF) in the perihematomal region has been associated with hematoma features and outcome-related imaging changes, underscoring the importance of local hypoperfusion for tissue vulnerability [52]. For this review, the key point is that the perihematomal region provides a metabolic setting in which lactate may act not only as a stress marker but also as a signaling molecule. If lactate-associated signaling persists or affects connected mood-related circuits, it may contribute to the biological vulnerability underlying post-ICH depression; however, this remains a testable hypothesis rather than an established clinical pathway.

Mitochondrial dysfunction and oxidative stress alter lactate handling

Mitochondrial dysfunction is a central component of metabolic stress after ICH. Hemin and iron toxicity can damage mitochondrial membranes, impair oxidative phosphorylation, disturb electron transport, and reduce ATP generation; however, direct inhibition of specific respiratory complexes may vary across models and should be described cautiously [61, 62]. When electron transport is compromised, electron leakage promotes excessive reactive oxygen species (ROS) production, which further damages mitochondrial proteins, lipids, and DNA [63]. In perihematomal neurons, ultrastructural mitochondrial abnormalities, including swelling and cristae disruption, have been observed after acute ICH, supporting a direct role for mitochondrial injury in secondary brain damage [61, 62]. ROS accumulation also interferes with mitochondrial quality control. Impaired or insufficient mitophagy may permit dysfunctional mitochondria to persist, thereby amplifying oxidative stress and energy failure. This feed-forward process can increase glycolytic reliance while limiting lactate utilization, creating conditions for increased local lactate availability. Although this mechanism is biologically plausible, direct evidence linking mitophagy failure to lactate accumulation in post-ICH depression is still lacking. Thus, mitochondrial injury should be framed as a mechanistic bridge between hemorrhagic toxicity, oxidative stress, and lactate-associated signaling rather than as a proven psychiatric driver.

Lactate generated in this context is not merely a byproduct of energy failure. It can influence histone and non-histone lactylation, thereby reshaping transcriptional programs related to inflammation, cell survival, glial activation, and synaptic plasticity [64, 65]. In parallel, oxidative stress activates compensatory antioxidant pathways, including the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) axis. Nicotinamide mononucleotide attenuated experimental ICH injury through Nrf2/HO-1 activation, supporting the relevance of antioxidant defense in hemorrhagic brain injury [66]. Huperzine A also reduced mitochondrial swelling, cristae injury, and apoptosis in perihematomal neurons, further highlighting mitochondrial protection as a potential strategy for limiting secondary injury [61, 67]. Oxidative stress also aggravates BBB disruption and vascular endothelial injury after ICH [63, 68]. More recently, biomaterial-based approaches, including neutrophil-like membrane-coated molybdenum nanoclusters and platelet-membrane-coated polydopamine nanoparticles, have been designed to scavenge ROS, protect damaged vessels, and improve neurological recovery in preclinical ICH models [69, 70]. These interventions support the importance of oxidative stress in ICH pathology, but their effects on depression-like behavior and cognitive outcomes remain largely untested.

Overall, mitochondrial dysfunction, oxidative stress, and increased lactate availability may form a self-reinforcing injury loop after ICH. Hemin and iron promote mitochondrial injury and ROS production; ROS worsens BBB dysfunction and cellular damage; impaired oxidative metabolism increases glycolytic stress and lactate availability. Lactate may then act as a signaling metabolite that modifies gene expression through lactylation-dependent mechanisms. This framework links acute hemorrhagic metabolic injury to glial and neuronal vulnerability, but its contribution to post-ICH depression requires longitudinal behavioral and clinical validation.

Lactate as a signaling molecule: from metabolic waste to epigenetic substrate

Lactate was historically viewed as an end-product of glycolysis, but it is now recognized as a signaling metabolite that connects cellular metabolism to gene regulation. Cellular lactate availability is shaped by glycolytic flux, lactate dehydrogenase A (LDHA)-dependent metabolism, and monocarboxylate transporters (MCTs), especially MCT1 [71]. Importantly, the biochemical route from lactate to lysine lactylation is still being refined. Current models implicate lactate availability, LDH-dependent metabolism, lactyl-CoA-related intermediates, p300/CBP activity, class I histone deacetylase activity, and other candidate writer/eraser systems rather than simple passive nuclear delivery of lactate [10, 72]. This metabolic-epigenetic interface is exemplified by histone lysine lactylation, in which lactate-derived lactyl groups are covalently attached to lysine residues and alter chromatin accessibility and transcriptional output.

Histone lactylation can regulate genes involved in inflammation, survival, tissue repair, and cellular adaptation. In macrophages, lactylation has been linked to inflammatory-to-reparative transitions in non-ICH inflammatory contexts, supporting its broader role as a metabolic timer of immune responses [73, 74]. In the nervous system, lactylation has been associated with neural excitation, hippocampal protein modification, and adult hippocampal neurogenesis, indicating that lactate-linked modifications may influence neuronal and glial function beyond peripheral immune biology [75, 76]. Astrocytic LDHA-dependent lactate homeostasis has also been implicated in neuronal excitability and depressive-like behaviors in mice, providing broader support for a lactate-behavior connection outside the ICH field [77]. The role of MCTs should be described carefully. These transporters regulate cellular lactate flux and intracellular lactate availability, but current evidence does not support a simple model in which they directly transport lactate into the nucleus. A more defensible interpretation is that MCT-dependent lactate exchange shapes cellular metabolic state, while nuclear lactylation depends on compartmentalized metabolism and enzymatic systems that remain under investigation [65, 71]. This distinction is important because overstating nuclear transport would weaken the mechanistic accuracy of the review.

The emerging view of lactate as an epigenetic regulator does not mean that lactate is uniformly harmful. In injury settings, lactate may be detrimental when coupled to acidosis, mitochondrial failure, oxidative stress, and unresolved inflammation; it may also support adaptive responses such as energy transfer, immune resolution, or neurogenesis depending on timing and cell type [78, 79]. Therapeutically, lactate metabolism and lactylation-associated machinery are attractive but early-stage targets. Modulating MCTs, LDHA, p300/CBP, histone deacetylases, or downstream lactylation readers may help test whether lactate-dependent gene regulation contributes to ICH injury [80, 81]. Nevertheless, systemic interference with lactate biology could disrupt immune responses, vascular function, astrocyte-neuron metabolic coupling, and exercise-related adaptation. Therefore, any intervention for post-ICH neuropsychiatric dysfunction would require careful timing, brain targeting, cell-type specificity, and behavioral validation. In summary, lactate should be viewed as a context-dependent metabolic signal rather than simply as waste or fuel. After ICH, disturbed perfusion, mitochondrial injury, oxidative stress, and inflammatory-cell activation may increase lactate availability in the perihematomal region. Lactate-linked histone and non-histone lactylation can then provide a plausible route by which acute metabolic stress alters inflammatory, glial, synaptic, and circuit-related transcriptional programs. This concept offers a mechanistic foundation for the proposed metabolic stress–lactylation–m6A framework, while leaving open the central question of whether this pathway causally contributes to post-ICH depression in vivo.

Histone lactylation and glial–neuronal dysfunction

H3K18la and H3K14la regulation of inflammatory and survival pathways

Histone lysine lactylation (Kla) has emerged as a metabolic-epigenetic modification that links lactate availability to chromatin regulation and gene transcription [82]. In ICH, the most direct astrocyte-related evidence currently links elevated histone H3 lysine 18 lactylation (H3K18la) to METTL3-dependent m6A modification of LCN2 and A1-like astrocyte activation, whereas direct proof that H3K18la broadly drives C3 or IL-6 transcription after ICH remains insufficient [9]. This distinction is important: H3K18la should be framed as a site-specific signal connected to METTL3-LCN2-mediated astrocyte reactivity, not as a general marker of all inflammatory gene activation. More broadly, lactate produced under metabolic stress can provide substrate availability for histone lactylation and thereby influence transcriptional programs related to inflammation, immune adaptation, and cell survival [65]. Cerebral ischemia-reperfusion and other CNS injury models support the broader principle that lactylation can regulate inflammatory genes, but these examples should be clearly separated from direct ICH evidence [83]. For H3K14la, the strongest ICH-specific evidence currently comes from neurons rather than microglia. H3K14la increases after ICH and in hemin-challenged neurons, where it suppresses plasma membrane Ca2+-ATPase 2 (PMCA2)-mediated calcium efflux, aggravates intracellular calcium overload, and promotes neuronal ferroptosis [10]. Therefore, H3K14la should be discussed primarily as a calcium-ferroptosis mechanism in neurons after ICH. Claims that H3K14la broadly activates microglial ferroptosis-related genes such as ACSL4 or TFRC after ICH are not yet sufficiently supported by direct evidence and should be avoided. Related studies in other models suggest that H3K14la may regulate cell-survival or cell-death genes in a context-dependent manner, but such findings should be treated as mechanistic background rather than ICH-specific proof.

Whether neuroprotective genes such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) undergo insufficient promoter lactylation after ICH remains unknown. If this occurs, it could reduce trophic support and impair neuronal recovery, but the current evidence does not justify presenting selective BDNF/GDNF hypolactylation as an established post-ICH mechanism. A more cautious formulation is that site-specific imbalance between injury-promoting and repair-associated lactylation programs may influence glial responses and neuronal plasticity. Similar locus-specific epigenetic effects have been described in other disease contexts, where lactylation changes correlate with transcriptional programs that shape cell fate [84]. Mechanistically, candidate systems implicated in lactylation include p300/CBP-related activity, class I histone deacetylase-associated activity, and lactyl-CoA-generating pathways; however, their relative contributions to H3K18la and H3K14la in specific ICH cell types remain unresolved. Therefore, lactylation enzymology should be described as an evolving field rather than a settled pathway in the post-ICH brain [64, 85, 86]. Bromodomain-containing proteins such as TRIM33 have been identified as readers of histone lactylation marks and can recognize H3K14la, providing a potential mechanism by which lactylated histones recruit transcriptional machinery [87]. Whether these reader-dependent mechanisms operate in neurons, astrocytes, or microglia after ICH remains to be tested.

The functional consequences of H3K18la and H3K14la extend beyond simple transcriptional activation. In bilirubin-related astrocyte injury models, H3K18la-mediated nucleotide-binding oligomerization domain 2 (NOD2) expression promotes astrocyte pyroptosis through mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling; this provides indirect support for H3K18la-driven inflammatory astrocyte injury, but it is not direct evidence for post-ICH depression [88]. These findings support a broader view of lactylation as a metabolic-epigenetic switch that can modulate glial inflammatory states, while emphasizing that site-, cell type-, and disease-specific validation remains essential. Therapeutically, histone lactylation pathways offer a promising but still early-stage opportunity to modulate glial reactivity and neuroinflammation. Pharmacological or genetic suppression of lactate production or H3K14la reduced neuronal ferroptosis in ICH models, supporting the value of testing lactate-lactylation mechanisms in hemorrhagic injury [10]. However, ICH-specific evidence for improving depression-like behavior or cognitive outcomes remains limited. Strategies aimed at regulating site-specific lactylation, lactylation readers such as TRIM33, or downstream inflammatory programs should therefore be described as future therapeutic concepts rather than clinically ready interventions.

In summary, H3K18la and H3K14la currently provide two important but distinct entry points into post-ICH lactylation biology. H3K18la is best supported as part of a METTL3-LCN2-associated astrocyte activation pathway after ICH, whereas H3K14la is best supported as a neuronal PMCA2-calcium-ferroptosis mechanism. Claims regarding broad inflammatory transcription, BDNF/GDNF promoter hypolactylation, or microglial ferroptosis-gene activation should remain hypothesis-generating unless validated directly in ICH models. The relevance of lactylation to post-ICH depression and related neuropsychiatric sequelae will require behavioral phenotyping, circuit-level analysis, cell-type-specific epigenomic profiling, and human validation.

Impact on calcium homeostasis, ferroptosis, and synaptic integrity

Direct ICH evidence in this domain remains narrow. H3K14la suppresses PMCA2-mediated calcium efflux, aggravates intracellular calcium overload, and promotes neuronal ferroptosis after ICH [10]. Separately, a collagenase-induced rat ICH study identified time-dependent perihematomal changes in the synaptogenic receptor α2δ1 and the thrombospondins TSP1/TSP2: TSP1 and α2δ1 protein levels increased and peaked on days 5 and 7, respectively, whereas TSP2 decreased on days 5–7, increased on day 14, and returned toward baseline by day 21 [89]. Because α2δ1/TSP1/2 participate in synaptogenesis in other settings, these data provide ICH-specific molecular context. However, that study measured expression rather than synapse number, dendritic spine density, neurotransmission, electrophysiology, LTP, or affective/cognitive behavior, and it did not examine lactylation or m6A.

Accordingly, no direct study currently demonstrates that lactylation-dependent manipulation after ICH restores PSD95 or Synapsin I, normalizes dendritic architecture, rescues LTP, or improves a neuropsychiatric phenotype independently of reduced acute lesion severity. The defensible conclusion is that H3K14la–PMCA2 links lactylation to calcium dyshomeostasis and ferroptotic injury, while the downstream synaptic consequence remains a testable hypothesis. Future experiments should pair cell-type-specific lactylation perturbation with blinded quantification of synaptic proteins and spine density, patch-clamp or field-potential recordings, LTP, lesion burden, and longitudinal depression-like, anxiety-like, and cognitive outcomes.

Connection to emotional and cognitive dysfunction in post-ICH depression

Post-ICH depression is a complex neuropsychiatric syndrome involving emotional, motivational, and cognitive dysfunction. Synaptic plasticity deficits in regions such as the hippocampus and medial prefrontal cortex (mPFC) may contribute to this phenotype, because these regions regulate memory, executive control, stress adaptation, and mood-related behavior [21, 47]. After ICH, metabolic stress may alter lactylation-related transcriptional programs, but direct evidence that lactylation itself causes synaptic protein loss or dendritic spine atrophy in post-ICH depression remains limited. The amygdala, particularly the basolateral amygdala, is central to fear, threat processing, and anxiety. Hemorrhagic lesions and secondary network injury may disturb excitatory/inhibitory (E/I) balance across limbic circuits, but direct evidence for lactylation-mediated amygdala E/I disruption after ICH is lacking [90]. Clinical and lesion-network studies support an association between post-stroke mood symptoms and damage involving fronto-striato-thalamic or limbic-related networks, but these findings should be integrated with lesion volume, white matter disease, premorbid vulnerability, and systemic complications [91, 92]. Accordingly, lactylation should be presented as a candidate molecular mechanism that may modulate circuit repair or vulnerability, not as a proven driver of post-ICH anxiety.

Histone lactylation provides a plausible mechanism by which local metabolic disturbances may influence broader neural network function. Elevated lactate and H3K14la after ICH have been linked to neuronal ferroptosis and calcium dyshomeostasis through PMCA2 repression [10]. These injury processes could secondarily impair synaptic maintenance and circuit remodeling in mood- and cognition-related networks. In parallel, H3K18la-associated METTL3-LCN2 signaling in astrocytes may contribute to inflammatory glial states that further compromise synaptic support [9]. This framework connects metabolic stress to glial-neuronal dysfunction, but it should remain a testable model rather than a confirmed mechanism of human post-ICH depression. In addition to histone lactylation, other injury pathways contribute to post-ICH neuropsychiatric vulnerability. Neuroinflammation, oxidative stress, apoptosis, ferroptosis, autophagy, BBB dysfunction, and edema can interact with epigenetic regulation to amplify neuronal injury and glial reactivity [29]. These processes may form feedback loops in which inflammatory cytokines alter cellular metabolism, lactate availability, and histone-modifying enzymes, thereby sustaining maladaptive glial and synaptic responses. However, direct evidence for such feedback in post-ICH depression remains incomplete.

Clinically, post-ICH depression and cognitive impairment are associated with poorer functional recovery and reduced quality of life, supporting the importance of understanding their biological substrates [25]. Histone lactylation may represent one such substrate, but therapeutic claims should remain cautious. Targeting lactate metabolism or lactylation pathways may reduce neuronal ferroptosis in preclinical ICH models, yet evidence for restoring synaptic protein expression, rebalancing amygdala E/I signaling, or improving post-ICH depressive behavior is still insufficient. Downstream signaling pathways also deserve attention. Pathways such as PI3K/Akt and GSK-3β regulate neuronal survival, synaptic remodeling, and inflammatory responses, and pharmacological modulation of these pathways has shown neuroprotective or regenerative effects in ICH-related models [93, 94]. However, these interventions should be discussed as broader neuroprotective strategies rather than direct evidence for lactylation-based treatment of post-ICH depression. Future studies should test whether lactylation interacts with these pathways in defined cell types and mood-related circuits.

In summary, metabolic stress-induced lactylation offers a plausible framework for linking hemorrhagic injury to glial activation, neuronal ferroptosis, synaptic vulnerability, and circuit dysfunction. The strongest current ICH evidence supports H3K14la-PMCA2-mediated calcium dysregulation and ferroptosis, together with H3K18la-associated METTL3-LCN2 astrocyte activation. The extension of these mechanisms to post-ICH depression remains promising but unproven. Establishing causality will require longitudinal behavioral assays, LTP and synaptic structural analyses, cell-type-specific lactylome mapping, and validation in human post-ICH cohorts.

m6A RNA methylation in post-ICH neuroinflammation and psychiatric symptoms

METTL3, FTO, and ALKBH5 in neuroinflammatory regulation

m6A RNA modification is a dynamic epitranscriptomic mechanism that regulates RNA stability, translation, splicing, and stress responses in the brain. After ICH, the evidence should be organized according to disease relevance. METTL3-dependent TFRC regulation provides a direct example linking m6A machinery to ferroptosis during ICH progression [4]. Other ICH-related examples include METTL3/YTHDF1-dependent BCL-3 regulation and WTAP-UQCRQ-mediated mitochondrial ROS and inflammatory responses in microglia [12, 95]. By contrast, studies from tumors, cardiomyocyte injury, hepatic metabolism, or autoimmune disease should be used only as mechanistic background rather than direct evidence for post-ICH neuroinflammation. Fat mass and obesity-associated protein (FTO) appears to have context-dependent effects in ICH and participates in hemorrhage-induced thalamic pain; nevertheless, its relevance to post-ICH depression remains incompletely defined [96]. Therefore, FTO should be presented as a candidate regulator of post-ICH neuronal vulnerability rather than as a proven upstream driver of specific inflammatory transcripts such as NLRP3 or HMGB1.

AlkB homolog 5 (ALKBH5) is an important m6A demethylase and may plausibly regulate neuronal or astrocytic RNA fate after brain injury, although the strongest current support comes mainly from non-ICH CNS injury contexts [97]. Direct evidence that ALKBH5 controls GLT-1/EAAT2 mRNA after ICH is currently insufficient. Therefore, ALKBH5 should be presented as a candidate regulator of glutamate homeostasis and glial-neuronal communication rather than as a proven mechanism of post-ICH excitotoxicity. This cautious framing preserves the biological rationale without overextending the evidence. Collectively, METTL3, FTO, ALKBH5, Wilms tumor 1-associated protein (WTAP), and m6A readers may shape post-ICH neuroinflammation by regulating RNA stability, translation, and stress responses. At present, the strongest ICH-relevant evidence centers on METTL3–TFRC-mediated ferroptosis, METTL3–YTHDF1–BCL-3-associated ferroptosis, and context-dependent FTO-related ferroptosis/autophagy pathways [4, 12, 98]. Whether these RNA-regulatory pathways persist long enough to influence post-ICH depression, anxiety, or cognitive impairment remains an important but unresolved question.

m6A-dependent regulation of LCN2, glial activation, and cell death

Lipocalin 2 (LCN2) is a secreted inflammatory mediator closely associated with reactive astrocytes, iron handling, and neuroinflammatory injury. In ICH, earlier experimental work identified LCN2 as a contributor to brain injury after hemorrhage [99]. More recent evidence indicates that histone lactylation is associated with METTL3-dependent m6A modification of LCN2 and A1-like astrocyte activation after ICH [9]. Thus, the most defensible ICH-specific statement is that the H3K18la-METTL3-LCN2 axis links metabolic-epigenetic stress to astrocyte reactivity. The precise m6A reader proteins responsible for LCN2 mRNA fate after ICH remain to be defined. Functionally, LCN2 may contribute to hemorrhagic injury through inflammatory signaling and iron-related pathways. However, the extent to which LCN2 directly increases neuronal iron uptake or drives complement-mediated synaptic pruning after ICH remains unclear. LCN2 has been linked to astrocyte-mediated neuroinflammation and pyroptotic injury in related brain injury contexts, supporting its broader relevance to glial pathology [100]. In the ICH setting, LCN2 should therefore be described as a mediator of astrocyte activation and inflammatory injury, rather than as definitive proof of m6A-driven neuronal iron uptake or synaptic engulfment.

Beyond LCN2, m6A modification may regulate transcripts involved in necroptosis, ferroptosis, mitochondrial dysfunction, and inflammatory signaling. For example, m6A-modified miR-873 has been linked to RIPK3-mediated necroptosis after ICH [101], while FTO-related RNA regulation has shown context-dependent effects on hemorrhage-induced pain and neuronal ferroptosis/autophagy [96, 98]. WTAP-mediated m6A modification of UQCRQ may also promote mitochondrial ROS and inflammatory responses in microglia after ICH [95]. By contrast, Bax/Bcl-2 regulation by m6A should not be presented as a post-ICH mechanism unless supported by ICH-specific evidence. Taken together, m6A-dependent regulation of LCN2 and cell-death-related transcripts provides a plausible post-transcriptional layer linking hemorrhagic injury to glial activation and neuronal loss. The METTL3-LCN2 axis is currently the clearest ICH-specific glial example, whereas YTHDF-dependent translation, complement-mediated synaptic loss, and Bax/Bcl-2 control remain less directly proven in this disease context. Targeting m6A machinery or downstream effectors such as LCN2 may offer therapeutic potential, but its relevance to post-ICH depression and cognitive impairment still requires behavioral, circuit-level, and human validation.

Neural network remodeling after ICH: a future research framework

Current ICH evidence supports m6A involvement in ferroptosis, necroptosis, mitochondrial reactive oxygen species, and glial inflammatory signaling, but not direct regulation of neural network remodeling [98]. No ICH study has yet shown that manipulating METTL3, WTAP, FTO, ALKBH5, or an m6A reader changes PSD95 or Synapsin I abundance, dendritic spine structure, electrophysiology or LTP, excitatory/inhibitory balance, or fronto-striato-thalamic connectivity. Broader nervous-system literature links m6A to learning, memory, aging, and activity-dependent synaptic regulation [49, 102], which establishes biological plausibility but not an ICH mechanism. This proposed bridge should therefore be tested by combining cell-type-specific m6A mapping and target validation with synaptic protein and spine measurements, circuit electrophysiology, connectivity analyses, and longitudinal behavioral phenotyping. Evidence that a defined m6A manipulation rescues circuit and behavioral outcomes after accounting for hematoma volume and acute neurological severity would be required before attributing post-ICH neuropsychiatric dysfunction to m6A-mediated network remodeling. Table 1 summarizes the direct mechanistic anchors and the remaining evidence gaps.

Table 1.

Mechanistic anchors linking lactylation, m6A RNA modification, and post-ICH neuropsychiatric vulnerability

Mechanistic module	Main cell type / context	Supported mechanism	Interpretation for post-ICH neuropsychiatric sequelae	References
Hemorrhage-specific metabolic stress	Perihematomal tissue; neurons, glia, and vascular cells	Iron/hemin, thrombin, hypoxia, mitochondrial injury, ROS, and BBB dysfunction create a metabolic–inflammatory microenvironment.	Provides a permissive setting for altered lactate handling and regulatory remodeling; it is not specific to neuropsychiatric outcomes.	[29, 30, 51]
H3K14la–PMCA2 axis	Neurons after ICH or hemin challenge	H3K14la represses PMCA2-mediated Ca²⁺ efflux, aggravating calcium overload and neuronal ferroptosis.	Strong ICH injury anchor; extension to depression-like behavior and circuit outcomes remains to be tested.	[10]
H3K18la–METTL3–LCN2 axis	Reactive astrocytes after ICH	H3K18la is associated with METTL3-dependent m6A modification of LCN2 and an A1-like reactive program.	Most direct lactylation–m6A crosstalk anchor in ICH; human neuropsychiatric relevance is unvalidated.	[9, 99]
METTL3/YTHDF1-related m6A injury pathways	ICH models and hemin-treated cells	METTL3–TFRC and METTL3–YTHDF1–BCL-3 pathways promote ferroptosis in ICH models.	Supports m6A-dependent cell-death regulation after ICH; psychiatric relevance remains indirect.	[4, 12]
m6A–miRNA and WTAP-mediated pathways	Neurons or microglia in ICH models	m6A-modified miR-873 regulates RIPK3-mediated necroptosis; WTAP–UQCRQ promotes mitochondrial ROS and inflammation.	Connects m6A to necroptosis, mitochondrial stress, and glial inflammation; circuit-level validation is needed.	[95, 101]
FTO/ALKBH5-related RNA regulation	Neurons/glia; ICH and related CNS-injury contexts	FTO is linked to hemorrhage-induced pain and context-dependent ferroptotic/autophagic responses; ALKBH5 evidence is mainly non-ICH.	Should be framed as candidate, context-dependent mechanisms rather than a unified post-ICH psychiatric pathway.	[96–98]
Circuit vulnerability	Fronto-striato-thalamic, hippocampal, and amygdala-related networks	Lesion-network disconnection, synaptic injury, inflammation, and cell death may converge on mood and cognitive circuits.	Provides the clinical-anatomical bridge to depression, anxiety, apathy, and cognitive impairment, but not molecular causality.	[46, 47, 91]

ICH, intracerebral hemorrhage; BBB, blood–brain barrier; ROS, reactive oxygen species; m6A, N6-methyladenosine; PMCA2, plasma membrane Ca²⁺-ATPase 2; LCN2, lipocalin 2; TFRC, transferrin receptor; CNS, central nervous system

A constrained working model of lactylation–m6A relationships after ICH

Metabolic stress-driven lactylation–m6A regulatory remodeling after ICH

ICH induces metabolic, epigenetic, and epitranscriptomic changes that contribute to secondary brain injury, but the direct crosstalk evidence is restricted to one reported pathway: H3K18la-associated, METTL3-dependent m6A regulation of LCN2 in reactive astrocytes [9]. H3K14la–PMCA2 and the METTL3–TFRC, METTL3–YTHDF1–BCL-3, WTAP–UQCRQ, m6A-modified miR-873–RIPK3, and FTO-related mechanisms are separate acute ICH injury modules [4, 10, 12, 95–98, 101]. Their joint placement in the present framework does not demonstrate that they form a single interconnected regulatory system. No ICH study has shown that lactylation broadly controls METTL3, WTAP, FTO, or m6A readers across cell types or mood-related circuits. We therefore use “lactylation–m6A framework” as a hypothesis-generating organizational model that separates the demonstrated H3K18la–METTL3–LCN2 pathway from a wider proposed network requiring independent replication and causal testing.

This lactylation-mediated epigenetic reprogramming provides a plausible route by which acute metabolic stress could be converted into longer-lasting changes in gene expression. Nevertheless, statements about direct METTL3 protein lactylation, METTL3 stabilization, or hemin-treated neuronal lactylation mechanisms should be restricted to studies that actually test those events. In the current ICH literature, the better-supported bridge is H3K18la-associated regulation of METTL3/LCN2 signaling in reactive astrocytes [9]. The involvement of p300/CBP, class I histone deacetylases, and other lactylation-related enzymes remains mechanistically attractive, particularly because they have been implicated in H3K14la regulation after ICH, but their cell-type-specific roles in neurons, astrocytes, and microglia still require validation [10]. Importantly, this model integrates metabolic stress, chromatin remodeling, and RNA modification into a unified framework for post-ICH glial reactivity. Activated microglia can induce neurotoxic reactive astrocyte programs through IL-1α, TNF, and C1q signaling, while reactive gliosis can contribute to stroke-subtype-dependent synapse elimination, providing a broader basis for inflammatory glial crosstalk and synaptic vulnerability [44, 103]. In ICH, H3K18la-associated METTL3-dependent LCN2 m6A modification provides a disease-relevant example of how lactylation and m6A machinery may converge on astrocyte activation. Targeting components of this axis, including lactate production, lactylation-associated enzymes, m6A imbalance, or downstream glial mediators, may help test whether this crosstalk contributes to secondary injury. Effects on depressive symptoms, cognition, and circuit repair after ICH, however, remain to be proven.

In summary, the established layer of the model comprises two site-specific lactylation findings—neuronal H3K14la–PMCA2 and astrocytic H3K18la–METTL3–LCN2—together with separate m6A-dependent acute injury pathways. The proposed layer is their possible convergence on persistent glial dysfunction, synaptic vulnerability, circuit disconnection, and neuropsychiatric symptoms. The human layer remains unproven because no clinical study has jointly measured lactylation, m6A targets, circuit dysfunction, and post-ICH depression or related outcomes. The framework should therefore be judged by the experiments it generates, not interpreted as an established causal explanation.

A1-like astrocyte activation and microglial dysregulation as effectors

Astrocytes and microglia are likely downstream effectors of lactylation–m6A crosstalk, but their responses should be described as heterogeneous reactive programs rather than fixed phenotypes. A1-like astrocyte programs may include complement-related and inflammatory modules that impair synaptic support, whereas microglia and monocyte-derived macrophages participate in hematoma clearance, cytokine release, debris removal, iron handling, and synaptic remodeling depending on timing and context [39, 104]. Human ICH transcriptomic data also show staged myeloid activation during hematoma response and resolution, supporting the concept that post-ICH inflammation evolves dynamically rather than through a single static glial state [54]. The key translational question is whether lactylation- and m6A-dependent programs prolong maladaptive glial reactivity after the acute bleed and thereby impair synaptic maintenance in prefrontal, hippocampal, striatal, thalamic, and amygdalar networks. Complement signaling, microglial activation, and astrocyte reactivity may all influence synaptic vulnerability, but the specific contribution of lactylation–m6A crosstalk to these processes remains unproven after ICH [40, 103]. This formulation preserves the glial-circuit logic of the original draft while avoiding the unsupported claim that a single lactylation–m6A pathway already explains synaptic loss and post-ICH depression.

Synaptic and circuit vulnerability: the proposed bridge to neuropsychiatric sequelae

Synaptic integrity within mood- and cognition-related circuits is essential for emotional processing, reward evaluation, memory, and behavioral regulation. After ICH, synaptic dysfunction may arise from lesion-network disconnection, ferroptosis, inflammatory cytokines, complement signaling, oxidative injury, impaired neurotrophic support, and metabolic stress. The prefrontal-striatal-thalamic loop, hippocampus, and amygdala are particularly relevant to anhedonia, motivation, anxiety, memory, and executive control; lesion-location studies, network analyses, and evidence from dorsolateral prefrontal rTMS support the relevance of these circuits to post-stroke depressive and cognitive symptoms [46, 47, 91, 105].

Direct evidence that lactylation–m6A crosstalk causes circuit dysfunction in these regions after ICH is still limited. A more defensible interpretation is that lactate accumulation and lysine lactylation may regulate transcriptional programs affecting glial reactivity, neuronal survival, and ferroptosis, whereas m6A methylation may modify RNA stability and translation of inflammatory or cell-death transcripts. These molecular effects could secondarily compromise synaptic maintenance and circuit repair [9, 11, 106]. Therefore, the lactylation–m6A axis should be presented as a candidate molecular bridge from hemorrhagic metabolic stress to synaptic vulnerability and psychiatric symptoms, not as a completed causal pathway. Future studies should connect this molecular model to circuit-level and behavioral endpoints. Key approaches include cell-type-specific lactylome and m6A profiling, spatial transcriptomics, electrophysiology, synaptic protein quantification, lesion-network mapping, and longitudinal assessment of depression-like, anxiety-like, cognitive, and sleep-related behaviors. Only by integrating molecular, glial, synaptic, and behavioral evidence can the field determine whether lactylation–m6A crosstalk is a driver of post-ICH depression or a parallel marker of secondary brain injury. Table 2 summarizes candidate intervention nodes and the validation steps needed before therapeutic translation.

Table 2.

Candidate intervention nodes and validation priorities for the lactylation–m6A framework after ICH

Candidate node	Rationale	Current evidence level	Key validation needed before translation	References
Lactate production / LDHA / MCT-dependent lactate flux	Temporally and cell-selectively modulating lactate flux may limit maladaptive lactylation while preserving metabolic support.	Mechanistically plausible; direct post-ICH neuropsychiatric evidence is lacking.	Define timing, cell type, dose, adaptive lactate functions, and long-term behavioral effects.	[10, 71, 81]
Site-specific histone lactylation	H3K14la and H3K18la are linked to neuronal ferroptosis and astrocyte reactivity, respectively.	Direct acute ICH injury evidence; behavioral and human validation remain insufficient.	Perform cell-type-resolved lactylome mapping, locus validation, LTP/spine analyses, and longitudinal behavior.	[9–10]
m6A writers, readers, and erasers	METTL3, YTHDF1, WTAP, FTO, and related regulators alter RNA fate across several ICH injury pathways.	Emerging target-specific ICH evidence; global effects are context dependent.	Map targets by cell type and time window; avoid nonspecific global m6A inhibition; confirm target engagement.	[12, 95, 98]
LCN2 and A1-like astrocyte programs	LCN2 links reactive astrocytes, inflammation, and iron-related stress.	Direct ICH glial evidence exists, but neuropsychiatric relevance remains indirect.	Test synaptic support, circuit physiology, mood/cognitive outcomes, and human biomarkers after LCN2 modulation.	[9, 99]
Anti-ferroptotic and mitochondrial protection	Ferroptosis and mitochondrial ROS are recurring downstream injury mechanisms after ICH.	Strong preclinical acute-injury rationale; long-term neuropsychiatric endpoints are under-tested.	Include cognition, anxiety/depression-like behavior, circuit physiology, and sex- and age-stratified analyses.	[10, 62, 95]

ICH, intracerebral hemorrhage; LDHA, lactate dehydrogenase A; MCT, monocarboxylate transporter; LTP, long-term potentiation; ROS, reactive oxygen species; m6A, N6-methyladenosine

Discussion

The literature supports several acute ICH molecular and cellular mechanisms, but it does not yet establish a causal lactylation–m6A pathway for human post-ICH depression. Direct evidence includes neuronal H3K14la–PMCA2-mediated calcium dysregulation and ferroptosis [10], astrocytic H3K18la-associated METTL3/LCN2 signaling [9], and distinct m6A-related cell-death or inflammatory pathways [4, 12, 95, 98, 101, 106]. Of these, only H3K18la–METTL3–LCN2 directly links lactylation with m6A machinery in an ICH model. Clinical studies independently establish that depression, anxiety, affective symptoms, and cognitive impairment can persist for months to years after ICH [13–20], but they do not identify this molecular axis. The central inference of this review is therefore a temporally and biologically plausible bridge, not a demonstrated chain of causation.

Four uncertainties constrain interpretation. First, the crosstalk model depends on a single preclinical axis and lacks independent replication across laboratories, ICH models, sexes, ages, and comorbidity states. Second, most mechanistic studies use acute collagenase-, autologous blood-, or hemin-based preparations and emphasize edema, ferroptosis, inflammation, or short-term neurological scores; these endpoints may not predict persistent psychiatric phenotypes. Third, direct synaptic and circuit validation is largely absent: there is no integrated evidence linking lactylation or m6A target engagement to dendritic structure, electrophysiology or LTP, lesion-network connectivity, and longitudinal depression-like, anxiety-like, or cognitive behavior after ICH. Fourth, no convincing human study has jointly measured lactylation, m6A regulation, glial or circuit biomarkers, and adjudicated post-ICH depression. The narrative-search design adds further limitations, including possible publication and language bias, heterogeneous experimental definitions, and the absence of formal study-level risk-of-bias scoring or quantitative pooling.

A decisive translational program would use complementary collagenase and autologous-blood models, both sexes, aged and comorbid animals, prespecified acute and chronic time points, and cell-type-specific perturbations. Molecular target engagement should be linked in the same experiment to lesion severity, glial-state profiling, synaptic structure, electrophysiology, circuit connectivity, and longitudinal behavior. Mediation or rescue designs should test whether circuit and behavioral effects persist after accounting for hematoma volume and general neurological improvement. Human studies should combine serial blood or cerebrospinal-fluid biomarkers, neuroimaging, standardized psychiatric and cognitive assessments, and where feasible perihematomal tissue profiling. Until such evidence is available, therapeutic proposals involving LDHA/MCT flux, lactylation enzymes, METTL3/FTO/WTAP, or LCN2 should be considered experimental strategies for mechanism testing rather than clinically actionable treatments.

Future directions and conclusion

This review provides a hypothesis-generating framework rather than a validated therapeutic model. Its near-term value is to define a falsifiable sequence from hemorrhage-specific metabolic stress to site-specific lactylation or m6A-dependent acute injury, followed by proposed glial, synaptic, circuit, and behavioral consequences. The priority is now to determine whether these molecular changes persist beyond the acute lesion, occur in relevant cell types and mood-related circuits, and causally influence long-term neuropsychiatric outcomes. Only convergent behavioral, electrophysiological, spatial-omics, and human longitudinal evidence would justify biomarker development or targeted therapeutic translation.

Abbreviations

BBB

Blood-brain barrier

BCL-3

B-cell lymphoma 3

CNS

Central nervous system

FTO

Fat mass and obesity-associated protein

H3K14la

Histone H3 lysine 14 lactylation

H3K18la

Histone H3 lysine 18 lactylation

ICH

Intracerebral hemorrhage

Kla

Lysine lactylation

LCN2

Lipocalin 2

LDHA

Lactate dehydrogenase A

MCT

Monocarboxylate transporter

METTL3

Methyltransferase-like 3

m6A

N6-methyladenosine

PMCA2

Plasma membrane Ca2+-ATPase 2

ROS

Reactive oxygen species

TFRC

Transferrin receptor

WTAP

Wilms tumor 1-associated protein

YTHDF1

YTH N6-methyladenosine RNA-binding protein 1

Author contributions

Conceptualization: Weihua Chen, Hongwei Teng, and Ziwei Yang. Literature investigation: Weihua Chen, Hongwei Teng, Xudong Yang, Feng Gao, and Chaoyu Han. Methodology: Weihua Chen, Hongwei Teng, and Hai Zhou. Data curation: Xudong Yang. Validation: Feng Gao and Shengkai Yang. Visualization: Weihua Chen and Hongwei Teng. Original draft preparation: Weihua Chen and Hongwei Teng. Review and editing: Xudong Yang, Feng Gao, Chaoyu Han, Shengkai Yang, Hai Zhou, and Ziwei Yang. Supervision and project administration: Ziwei Yang. Weihua Chen and Hongwei Teng contributed equally and share first authorship. All authors read and approved the final manuscript and agree to be accountable for the work.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Not applicable. This review does not report new studies involving human participants, human data, or animals.

Consent for publication

Not applicable.

Consent to participate

Not applicable.