Tumour Necrosis Factor-α Promotes Pyroptosis in Diabetic Liver Injury via the HMGB1/TLR4/MyD88/NF-κB Pathway

Area of Science:

• Hepatology and Immunology
• Molecular Mechanisms of Disease

Background:

• Diabetic liver injury (DLI) is an inflammatory complication driven by pro-inflammatory cytokines like tumour necrosis factor-alpha (TNF-α).
• Pyroptosis, a form of programmed cell death, is implicated in DLI pathogenesis.
• The specific role of TNF-α in promoting pyroptosis within DLI remains to be fully elucidated.

Purpose of the Study:

• To investigate the protective effects of TNF-α inhibition on DLI.
• To elucidate the molecular mechanisms underlying TNF-α's role in DLI, specifically focusing on pyroptosis.
• To assess the therapeutic potential of TNF-α inhibition for DLI.

Main Methods:

• In vitro studies using HepG2 hepatocytes and in vivo studies in Sprague-Dawley rats.
• Assessed pyroptosis markers (caspase-1, Gasdermin D [GSDMD]), high mobility group protein B1 (HMGB1), and the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) pathway.
• Evaluated liver function tests (ALT, AST, ALP, triglycerides), liver histopathology, and pyroptosis markers (NOD-like receptor family pyrin domain containing 3 [NLRP3]) in vivo.

Main Results:

• In vitro, TNF-α inhibition reduced high glucose-induced hepatocyte pyroptosis and HMGB1 release, suppressing the TLR4/MyD88/NF-κB pathway.
• In vivo, TNF-α inhibition (using rhTNFR:Fc) improved liver function and histopathology in diabetic rats without altering blood glucose levels.
• TNF-α inhibition downregulated HMGB1/TLR4/MyD88/NF-κB pathway components and NLRP3 expression in diabetic rat livers.

Conclusions:

• TNF-α exacerbates DLI by inducing hepatocyte pyroptosis via the HMGB1/TLR4/MyD88/NF-κB signalling axis.
• TNF-α inhibition provides significant hepatic protection in DLI, independent of glycemic control.
• Targeting TNF-α represents a promising therapeutic strategy for managing diabetic liver injury.