Targeting RIG-I alleviates renal tubular epithelial cells PANoptosis during post-traumatic rhabdomyolysis

Post-traumatic rhabdomyolysis poses a significant threat to human life and health, primarily due to crush syndrome-associated acute kidney injury (CS-AKI). A critical factor contributing to this condition is the destruction of the tubular epithelial barrier, which results from the death of tubular epithelial cells (TECs) caused by myoglobin (Mb) accumulation. In this study, we identified a novel programmed cell death (PCD), termed PANoptosis, occurring in TECs in both in vivo and in vitro CS-AKI models. This process is induced by Mb, with RIG-I serving as the apical sensor molecule for damage-associated molecular patterns (DAMPs). RIG-I transfers Mb insult signals into the cell, where it aggregates with ASC, caspase-1, caspase-8, FADD, RIPK1, and RIPK3 forming the RIG-I PANoptosome. Attenuating RIG-I expression not only disrupts PANoptosome assembly and inhibits PANoptosis but also mitigates TECs damage. Consequently, targeting RIG-I activity may offer a promising avenue for developing novel therapies for post-traumatic rhabdomyolysis and other Mb-associated diseases that trigger cell death and pathology.