H4K12 Lactylation Regulates NDUFS7 to Drive Microglia Reverse Electron Transport in Spinal Cord Injury

ABSTRACT

Microglial polarization toward the pro‐inflammatory state drives secondary injury following spinal cord injury (SCI), yet the mechanisms of metabolic reprogramming governing this phenotypic shift remain elusive. Here, we identify a lactate‐dependent signaling axis linking histone lactylation to mitochondrial reverse electron transport (RET) that sustains neuroinflammation. We demonstrate that SCI‐induced accumulation of lactate promotes histone H4 lysine 12 lactylation (H4K12la), which directly upregulates NDUFS7, a core subunit of mitochondrial Complex I. Elevated NDUFS7 triggers mitochondrial hyperactivity and RET, resulting in a reactive oxygen species (ROS) burst that enforces pro‐inflammatory polarization. To intervene in this cascade, we engineered a biomimetic nanotherapeutic, MM@mPTC, comprising an LDHA‐targeting PROTAC encapsulated within ROS‐responsive micelles and coated with microglial membranes (MM). The biomimetic MM@mPTC system actively targets activated microglia and undergoes ROS‐responsive payload release to specifically degrade LDHA. This targeted degradation dismantles the pathogenic “LDHA‐H4K12la‐NDUFS7‐RET” axis, halting RET‐driven ROS production and reprogramming microglia toward a reparative phenotype. Consequently, this intervention significantly mitigates neuroinflammation, preserves neuronal tissue, and promotes robust locomotor recovery, presenting a precise metabolic‐epigenetic therapeutic paradigm for central nervous system trauma.