Indole-3-carbaldehyde mitigates fibrosis progression in MASH with T2DM via the SIRT1/TGF-β/SMAD signaling pathway

  • Biochim Biophys Acta Mol Basis Dis. 2026 Nov;1872(8):168363. doi: 10.1016/j.bbadis.2026.168363.
Lu Li  1 ,  Zeyu Wang  2 ,  Yinglan Ji  1 ,  Raorao Wang  1 ,  Xiangjuan Qi  1 ,  Yana Zhu  1 ,  Yaping Wang  1 ,  Xiaoyang Zhang  3 ,  Man Li  4 ,  Yong Jiang  5
Affiliations
  • 1. Department of Gastroenterology, the Second Hospital of Tianjin Medical University, Tianjin, China.
  • 2. Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 3. Department of Pathology, the Second Hospital of Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
  • 4. Department of Gastroenterology, the Second Hospital of Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
  • 5. Department of Gastroenterology, the Second Hospital of Tianjin Medical University, Tianjin, China. Electronic address: [email protected].
PMID: 42435945 DOI: 10.1016/j.bbadis.2026.168363
Abstract

Background: Hyperglycemia is an independent risk factor for the accelerated progression of metabolic dysfunction-associated steatohepatitis (MASH) to liver fibrosis, with the underlying mechanisms not yet fully elucidated.

Methods: A diabetic metabolic dysfunction-associated steatohepatitis (T2DM-MASH) mouse model was successfully established, and metabolomics screening identified indole-3-carbaldehyde (3-IAld) as a potential therapeutic candidate. The efficacy of 3-IAld (25 and 50 mg/kg) was evaluated in vivo, and its anti-fibrotic mechanism was further validated in human hepatic stellate cells (LX-2) exposed to pro-fibrotic conditions.

Results: The T2DM-MASH model was validated by metabolic disturbances (hyperglycemia, dyslipidemia), hepatic injury, and histopathological steatohepatitis. Fecal 3-IAld levels were significantly reduced in T2DM-MASH mice and inversely correlated with metabolic and fibrotic markers. In vivo, 3-IAld supplementation significantly ameliorated metabolic parameters, liver Enzymes (ALT/AST), and pathological fibrosis in a dose-dependent manner (P < 0.05). Ultrastructural analysis revealed that 3-IAld restored intestinal barrier integrity by upregulating tight junction proteins (ZO-1, occludin) and reducing plasma LPS (P < 0.05). In vitro, 3-IAld significantly inhibited HSC activation, characterized by suppressed cell proliferation and downregulated fibro-genic markers (α-SMA, Col1a1, TGF-β1, TIMP-1). This protective effect was reversed by the SIRT1 Inhibitor EX-527, confirming the reliance on SIRT1 signaling. Mechanistically, 3-IAld alleviated Hepatic Fibrosis, at least in part, by suppressing the TGF-β/SMAD signaling pathway, as evidenced by reduced phosphorylation of SMAD2 and SMAD3.

Conclusions: Our findings, underscore the potential of the Microbial Metabolite 3-IAld to attenuate fibrosis progression in T2DM-MASH, at least in part, by regulating the SIRT1/TGF-β/SMAD pathway. However, definitive confirmation of this specific signaling axis in vivo remains to be established with genetic or pharmacological models.

Keywords
Indole-3-carbaldehyde; Liver fibrosis; Metabolic dysfunction-associated steatohepatitis; SIRT1/TGF-β/SMAD pathway; Type 2 diabetes mellitus.
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