Hepatocyte‐Specific GSDMD Deficiency Aggravates Sepsis by Disrupting Non‐Canonical Secretion of Anti‐Inflammatory Factors

This study proposes for the first time that hepatic GSDMD plays a key protective role in sepsis. Hepatic GSDMD may release inflammatory inhibitory factors including VEGF‐B and Gremlin‐1 through pore‐forming activity to inhibit the production of inflammatory factors from macrophages, thereby alleviating the inflammatory response of septic mice. Abstract Gasdermin D (GSDMD)‐mediated pyroptosis in macrophages plays a clear role in promoting inflammation and mortality in sepsis. The liver is a commonly damaged organ during sepsis and also an important organ for releasing acute response proteins. However, whether pyroptosis occurs and the function of GSDMD in hepatocytes remains unclear. It is surprising to find that hepatocyte‐specific GSDMD knockout (GSDMDhep‐/‐) mice have significantly reduced survival rates, markedly elevated systemic inflammation, and increased inflammation in the peritoneal cavity and lungs, suggesting that the absence of GSDMD in hepatocytes promotes systemic inflammatory responses. Serum proteomic analysis shows that anti‐inflammatory factors such as VEGF‐B and Gremlin‐1 are significantly reduced in GSDMDhep‐/‐ mice. Through in vitro and in vivo experiments combined with a constructed full‐length GSDMD and a mutant GSDMD plasmid (GSDMD‐c.D276A) that cannot be cleaved, VEGF‐B and Gremlin‐1 are verified to be released from hepatocytes through the pore‐forming activity of GSDMD, thus inhibiting the production of inflammatory factors by macrophages. More importantly, hepatocyte‐specific replenishment of full‐length GSDMD can reverse the exacerbated inflammatory response in GSDMDhep‐/‐ mice. These findings together establish that hepatic GSDMD plays a key protective role in sepsis by promoting the release of anti‐inflammatory factors through pore formation in hepatocytes. This study proposes for the first time that hepatic GSDMD plays a key protective role in sepsis. Hepatic GSDMD may release inflammatory inhibitory factors including VEGF-B and Gremlin-1 through pore-forming activity to inhibit the production of inflammatory factors from macrophages, thereby alleviating the inflammatory response of septic mice. Abstract Gasdermin D (GSDMD)-mediated pyroptosis in macrophages plays a clear role in promoting inflammation and mortality in sepsis. The liver is a commonly damaged organ during sepsis and also an important organ for releasing acute response proteins. However, whether pyroptosis occurs and the function of GSDMD in hepatocytes remains unclear. It is surprising to find that hepatocyte-specific GSDMD knockout (GSDMD hep-/- ) mice have significantly reduced survival rates, markedly elevated systemic inflammation, and increased inflammation in the peritoneal cavity and lungs, suggesting that the absence of GSDMD in hepatocytes promotes systemic inflammatory responses. Serum proteomic analysis shows that anti-inflammatory factors such as VEGF-B and Gremlin-1 are significantly reduced in GSDMD hep-/- mice. Through in vitro and in vivo experiments combined with a constructed full-length GSDMD and a mutant GSDMD plasmid (GSDMD-c.D276A) that cannot be cleaved, VEGF-B and Gremlin-1 are verified to be released from hepatocytes through the pore-forming activity of GSDMD, thus inhibiting the production of inflammatory factors by macrophages. More importantly, hepatocyte-specific replenishment of full-length GSDMD can reverse the exacerbated inflammatory response in GSDMD hep-/- mice. These findings together establish that hepatic GSDMD plays a key protective role in sepsis by promoting the release of anti-inflammatory factors through pore formation in hepatocytes. Advanced Science, Volume 12, Issue 43, November 20, 2025.