Cell death and its interaction with mitochondrial dysfunction in pathogenesis of acute pancreatitis: a comprehensive review.

Acute pancreatitis (AP) is a potentially life-threatening inflammatory disease whose severity is fundamentally shaped by the mode of pancreatic acinar cell death. Crucially, this cell fate decision is primarily governed by genetically encoded programs known as regulated cell death (RCD), including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent death. Unlike accidental necrosis, RCD proceeds via specific signaling cascades. In AP, excessive RCD in pancreatic acinar cells drives local tissue injury and systemic inflammation, potentially leading to systemic inflammatory response and organ failure. Mitochondria are central integrators of these interconnected RCD pathways: pathological calcium overload and oxidative stress disrupt mitochondrial function, causing ATP depletion. These organelle failures precipitate cell death cascades and amplify inflammation. Damaged mitochondria release damage-associated molecular patterns (DAMPs), which further promote cytokine release and pancreatic injury. This review highlights key RCD signaling mechanisms in AP and their pathophysiological significance. Emerging therapeutic strategies include agents that stabilize mitochondrial integrity or inhibit RCD signaling, which have shown efficacy in experimental models. Therefore, targeting RCD-especially via mitochondrial protection-represents a promising approach to limit pancreatic damage and improve outcomes. To realize this potential, we conclude by outlining translational challenges, such as biomarker validation, and proposing future research directions to advance AP therapeutics.