Melatonin Modulates Glucose Metabolism Reprogramming via Targeting G6PD to Alleviate Lead‐Induced Hepatocytes Pyroptosis in Common Carp ( Cyprinus carpio L.)

Abstract Lead (Pb) is a prevalent toxic contaminant that accumulates in freshwater ecosystems, posing severe toxicity to non‐target species such as fish and contributing to the pathogenesis of liver disease. Melatonin (Mel) is a well‐known natural antioxidant that has been found to improve liver function through its potent anti‐inflammatory properties. However, whether and how Mel alleviates Pb‐triggered hepatotoxicity remains unclear. Mitochondria play a vital role in glucose metabolism, and glucose metabolic reprogramming is characterized by elevated glycolysis, resulting in lactate accumulation, which is a precursor for histone lactylation, an epigenetic modification. In this study, it is demonstrated that Pb triggers glucose metabolism reprogramming, resulting in lactate accumulation. Specifically, lactate links glycolysis and mitochondrial homeostasis via histone H3 lysine 18 lactylation (H3K18la), which modulates the activity of dynamin‐related protein 1 (DRP1). Furthermore, DRP1 actively mediates mitochondrial fragmentation, thereby facilitating inflammatory signals derived from the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway. Additionally, the results first demonstrate that Mel redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) by targeting glucose‐6‐phosphate dehydrogenase (G6PD). In summary, Mel targets G6PD to suppress glycolysis‐driven H3K18la and DRP1 transcription, thereby maintaining mitochondrial homeostasis to alleviate hepatocytes pyroptosis dependent on cGAS‐STING pathway under Pb exposure.