2. Academic Validation
  3. The Endogenous Metabolite TDCA Ameliorates LPS-Driven Liver Injury via Modulation of Caspase-11/GSDMD-Mediated Pyroptosis

The Endogenous Metabolite TDCA Ameliorates LPS-Driven Liver Injury via Modulation of Caspase-11/GSDMD-Mediated Pyroptosis

  • Int J Mol Sci. 2026 Feb 28;27(5):2273. doi: 10.3390/ijms27052273.
Deqing Ruan 1 2,  Xing Yan 3,  Yanmei Tang 1 2,  Shunhua Yang 1 2,  Xinxin Yang 1 2,  Mei Zhang 1 2,  Shibo Yu 2,  Jie Yu 1 2
Affiliations

Affiliations

  • 1 Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming 650500, China.
  • 2 School of Chinese Materia Medica, Yunnan University of Chinese Medicine, 1076 Yuhua Road, Kunming 650500, China.
  • 3 Jiangxi Province Key Laboratory of Sustainable Utilization of Traditional Chinese Medicine Resources, Institute of Traditional Chinese Medicine Health Industry, China Academy of Chinese Medical Sciences, Nanchang 330115, China.
PMID: 41828497 DOI: 10.3390/ijms27052273
Abstract

The liver is a central immunometabolic organ during endotoxemia and a major target of sepsis-related injury. Intriguingly, the liver exhibits a notable resilience to endotoxemia or septic insults, suggesting the activation of endogenous protective mechanisms. The bile acid taurodeoxycholic acid (TDCA) demonstrates hepatoprotective properties; nonetheless, its role and mechanism in lipopolysaccharide (LPS)-driven inflammatory liver injury remain elusive. This study reveals that LPS challenge induces significant reprogramming of hepatic bile acid metabolism, with TDCA being markedly elevated in LPS-challenged mice. In vitro, TDCA dose-dependently attenuated Pyroptosis in bone marrow-derived macrophages, as evidenced by reduced Lactate Dehydrogenase (LDH) release, decreased interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion, and suppressed dye Oxazole yellow uptake. Consistent with reduced non-canonical inflammasome signaling, TDCA treatment was associated with decreased activation of caspase-11 and its downstream targets Gasdermin D (GSDMD) and IL-1β. In a lethal D-Galactosamine (D-GalN)/LPS-induced toxin-sensitized inflammatory liver injury model, therapeutic administration of TDCA (3, 6 mg/kg) profoundly improved survival rates (40% and 80%, respectively), attenuated liver injury, reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), suppressed systemic inflammation (IL-1β and IL-18), and ameliorated histopathological damage. Crucially, TDCA treatment reduced the activation of the caspase-11/GSDMD pathway in the septic liver. Our findings demonstrate that TDCA is an endogenously mobilized bile acid that confers protection against LPS-driven inflammatory liver injury, with effects supporting a role for modulation of the Caspase-11/GSDMD pyroptotic pathway. These observations provide hypothesis-generating implications for sepsis-associated liver injury that warrant further validation in clinically relevant sepsis models and pathway-necessity studies.

Keywords

Caspase-11; GSDMD; LPS-driven liver injury; TDCA; bile acid; pyroptosis.

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