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<p>Metabolic dysfunction–associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction–associated steatotic liver disease (MASLD), involves interconnected metabolic, inflammatory, and fibrogenic pathways unlikely to respond fully to single-target therapies. This study investigated the therapeutic potential of combining alvespimycin (ALV), an HSP90 inhibitor, with fluvastatin (FLU), a lipid-lowering agent, in a thioacetamide (TAA)-augmented high-fat diet rat model of MASH, hereafter referred to as the NASH model in keeping with established preclinical nomenclature. Disease induction caused marked hepatocellular injury, dyslipidemia, oxidative imbalance, inflammasome activation, pyroptosis, and fibrosis. Monotherapy with either ALV or FLU improved selected parameters, but each exerted incomplete effects. In contrast, combined ALV + FLU therapy produced coordinated protection, normalizing liver enzymes, improving lipid profile, restoring antioxidant capacity, and significantly reducing inflammatory and fibrogenic mediators including TNF-α, IL-1β, IL-18, TGF-β1, and hydroxyproline. Western blot analysis further showed that dual therapy markedly suppressed HSP90, NLRP3, caspase-1, NTGSDMD, and p-SMAD2/3. Mechanistically, the combination targets two distinct but converging levels of inflammasome regulation: FLU reduces ox-LDL, a key upstream activator of NLRP3, whereas ALV destabilizes the client protein NLRP3 by inhibiting its molecular chaperone HSP90. This dual-level interruption of the ox-LDL-NLRP3-caspase-1-IL-1β/IL-18 axis explains the superior anti-inflammatory, anti-pyroptotic, and antifibrotic efficacy of the combination. Exploratory HSA and Bliss analyses supported positive combination effects across oxidative, inflammatory, and fibrotic endpoints. Collectively, these findings suggest that ALV + FLU may represent a mechanistically rational, multitarget strategy capable of attenuating several hallmarks of MASH pathogenesis. Further studies are warranted to evaluate the translational potential of this combinatorial regimen for MASLD/MASH management.</p>

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Disruption of upstream ox-LDL signaling and HSP90-mediated NLRP3 stability protects against experimental steatohepatitis

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Alaa Karam,
  • Amir Mohamed Abdelhamid,
  • Sameh Saber

摘要

Metabolic dysfunction–associated steatohepatitis (MASH), the progressive inflammatory form of metabolic dysfunction–associated steatotic liver disease (MASLD), involves interconnected metabolic, inflammatory, and fibrogenic pathways unlikely to respond fully to single-target therapies. This study investigated the therapeutic potential of combining alvespimycin (ALV), an HSP90 inhibitor, with fluvastatin (FLU), a lipid-lowering agent, in a thioacetamide (TAA)-augmented high-fat diet rat model of MASH, hereafter referred to as the NASH model in keeping with established preclinical nomenclature. Disease induction caused marked hepatocellular injury, dyslipidemia, oxidative imbalance, inflammasome activation, pyroptosis, and fibrosis. Monotherapy with either ALV or FLU improved selected parameters, but each exerted incomplete effects. In contrast, combined ALV + FLU therapy produced coordinated protection, normalizing liver enzymes, improving lipid profile, restoring antioxidant capacity, and significantly reducing inflammatory and fibrogenic mediators including TNF-α, IL-1β, IL-18, TGF-β1, and hydroxyproline. Western blot analysis further showed that dual therapy markedly suppressed HSP90, NLRP3, caspase-1, NTGSDMD, and p-SMAD2/3. Mechanistically, the combination targets two distinct but converging levels of inflammasome regulation: FLU reduces ox-LDL, a key upstream activator of NLRP3, whereas ALV destabilizes the client protein NLRP3 by inhibiting its molecular chaperone HSP90. This dual-level interruption of the ox-LDL-NLRP3-caspase-1-IL-1β/IL-18 axis explains the superior anti-inflammatory, anti-pyroptotic, and antifibrotic efficacy of the combination. Exploratory HSA and Bliss analyses supported positive combination effects across oxidative, inflammatory, and fibrotic endpoints. Collectively, these findings suggest that ALV + FLU may represent a mechanistically rational, multitarget strategy capable of attenuating several hallmarks of MASH pathogenesis. Further studies are warranted to evaluate the translational potential of this combinatorial regimen for MASLD/MASH management.