Caspase noncanonical roles in mediating lipid homeostasis

Caspases are well recognized and studied as the central executioners of apoptosis, while recent studies have unraveled their diverse roles beyond cell apoptotic function. One emerging area of interest is nonapoptotic caspase activity as a potential regulator in lipid metabolism. This review explores the differential nonapoptotic role of caspases in lipid metabolic process, encompassing the influence of caspases on lipid reprogramming, lipid synthesis, degradation, transport, and signaling. We discuss the mechanisms underlying these interactions, their relevance to physiological processes, and their implications for various diseases. This reveals a hidden layer of regulation where the machinery of cell death is repurposed to control the fundamental processes of fat handling in living animal. Dysregulation of this system forms a vicious cycle that propagates cellular dysfunction, directly contributing to the pathogenesis of major human diseases in aging, including redox stress, nonalcoholic steatohepatitis, type 2 diabetes, neurodegenerative disorders, and cancer. Consequently, the caspase-metabolism axis emerges as a compelling therapeutic frontier. However, the clinical translation of caspase modulators is challenged by the context-dependent duality of caspase functions. Future therapeutic strategies must therefore advance beyond pan-inhibition toward the precise, context-specific modulation of discrete caspase-mediated metabolic events to halt disease progression effectively.