Elucidation of ACAT1's role in hepatic ischemia-reperfusion injury: TFEB-mediated mitophagy and ferroptosis modulation as therapeutic targets

Hepatic ischemia-reperfusion injury (HIRI) remains a critical clinical challenge, significantly impacting the success of liver transplantation and postoperative recovery following resection. The study investigated the roles of mitochondrial acetyl-CoA acetyltransferase1 (ACAT1) and transcription factor EB (TFEB) in orchestrating cellular responses to HIRI, specifically focusing on mitophagy and ferroptosis pathways. Using a combination of in vivo models and cellular molecular techniques,we found that ACAT1 plays a pivotal hepatoprotective role.By fostering TFEB-mediated mitophagic processes and curtailing ferroptosis, ACAT1 emerges as a critical moderator of cellular resilience against oxidative stresses induced by reperfusion. These findings elucidate the molecular interplay underlying HIRI and identify ACAT1 as a potential therapeutic target for mitigating hepatic damage and enhancing patient outcomes in liver surgery and transplantation scenarios. • Unveiling ACAT1 and TFEB roles in HIRI pathogenesis • ACAT1 emerges as a pivotal hepatoprotective factor • TFEB-mediated mitophagy counteracts cellular stress • ACAT1's modulation of ferroptosis key in HIRI resilience • Therapeutic potential highlighted for hepatic damage in surgery and transplantation