Targeting Wnt/beta-catenin signaling to attenuate short-chain chlorinated paraffins-triggered hepatocyte mitochondrial fission and subsequent pyroptosis.

Short-chain chlorofluorocarbons (SCCPs), have been found to cause liver toxicity. This investigation probes into the mechanisms of SCCPs-induced mitochondrial dysfunction and cellular pyroptosis. The introduction of SCCPs via gavage instigates inflammasome activation and pyroptosis in mouse liver and HepG2 cells. Also, SCCPs disrupt mitochondrial dynamics in HepG2 cells and impair mitochondrial function. The use of the mitochondrial division inhibitor Mdivi-1, which reduces disturbances in mitochondrial dynamics, improved the mitochondrial dysfunction and cellular pyroptosis caused by SCCPs. Moreover, exposure to SCCPs resulted in the downregulation of the β-catenin signal in mouse liver and HepG2 cells. Restoring β-catenin levels through plasmid transfection and lithium chloride treatment alleviated the disruptions in mitochondrial dynamics and function, as well as cellular pyroptosis induced by SCCPs. These findings confirm that SCCPs disrupt mitochondrial dynamics by downregulating β-catenin signaling, resulting in mitochondrial dysfunction and the activation of the NLRP3 inflammasome and pyroptosis, ultimately causing hepatocyte injury.