Capsaicin alleviates acute alcohol-induced pyroptosis by activating ESCRT-III-dependent cell membrane repair in hepatocytes

Capsaicin (CAP), the active ingredient in hot chilli peppers, has anti-inflammatory and hepatoprotection effects. Acute alcoholic liver injury (AALI) is liver damage caused by acute alcohol abuse, which can lead to severe liver lesions and even be life-threatening. Pyroptosis is inflammation-related programmed cell death characterized by membrane rupture and plays a key role in AALI. The endosomal sorting complexes required for transport (ESCRT) proteins can gather at damaged areas of the membrane to facilitate the process of sealing the membrane. In this study, we found that CAP could relieve acute alcohol-induced Pyroptosis of hepatocytes in vitro and in vivo. Mechanically, we found that CAP could alleviate acute alcohol-induced Pyroptosis by activating the ESCRT-III-dependent membrane repair machinery. Furthermore, the data showed that CAP induced ESCRT-III protein expression by activating transient receptor potential vanilloid member 1 (TRPV1) on the cell membrane and CA²⁺ influx. TRPV1 inhibitor capsazepine (CPZ) inhibited the relief effect of CAP on acute alcohol-induced Pyroptosis. Overall, these results showed that CAP might activate ESCRT-III-dependent membrane repair machinery through CA²⁺ influx, which is regulated by TRPV1 calcium channels, therefore mitigating acute alcohol-induced Pyroptosis. Our research provides a new perspective on a naturally active food product to promote cell repair and relieve AALI.