Gasdermin D–mediated pyroptosis suppresses liver regeneration after 70% partial hepatectomy

Pyroptosis is a kind of programmed cell death primarily mediated by gasdermin D (GSDMD) and shown to regulate multiple diseases. However, its contribution to liver regeneration, a fine-tuned tissue repair process mediated primarily by hepatocytes after mass loss, remains unclear. Herein, we found that caspase-11/GSDMD-mediated pyroptosis was activated in regenerating liver after 70% partial hepatectomy. Impeding pyroptosis by deleting GSDMD significantly reduced liver injury and accelerated liver regeneration. Mechanistically, GSDMD deficiency up-regulates the activation of hepatocyte growth factor/c-Met and epidermal growth factor receptor mitogenic pathways at the initiation phase. Moreover, activin A and glypican 3 (GPC3), two terminators of liver regeneration, were inhibited when GSDMD was absent. In vitro study suggested the expressions of activin A and GPC3 were induced by interleukin (IL)-1β and IL-18, whose maturations were regulated by GSDMD-mediated pyroptosis. Similarly, pharmacologically inhibiting GSDMD recapitulates these phenomena. Conclusion: This study characterizes the role of GSDMD-mediated pyroptosis in liver regeneration and lays the foundation for enhancing liver restoration by targeting GSDMD in liver patients with impaired regenerative capacity.