The Lactate‐Primed KAT8‒PCK2 Axis Exacerbates Hepatic Ferroptosis During Ischemia/Reperfusion Injury by Reprogramming OXSM‐Dependent Mitochondrial Fatty Acid Synthesis

Abstract Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia‐reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate‐primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene‐edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin‐mediated polyubiquitination of 3‐oxoacyl‐ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia‐mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT.