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Indole-3-carbaldehyde mitigates fibrosis progression in MASH with T2DM via the SIRT1/TGF-β/SMAD signaling pathway
Lu Li1, Zeyu Wang2, Yinglan Ji1
1Department of Gastroenterology, the Second Hospital of Tianjin Medical University, Tianjin, China.
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.
