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

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.