Lactylation and N6-Methyladenosine RNA modification in neuropsychiatric sequelae after intracerebral hemorrhage: a...

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.