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<p>Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a multifactorial condition linked to obesity, insulin resistance, dyslipidemia, and oxidative stress. While pharmacological interventions are limited, polyherbal formulations (PHF) offer a promising, multi-targeted approach for mitigating the pathogenesis of MASLD. The current study evaluated the therapeutic efficacy of a newly developed PHF comprising <i>Vernonia amygdalina</i>, <i>Cissus quadrangularis</i>, <i>Eryngium foetidum</i>, and <i>Aristolochia indica</i> in a high-fat diet (HFD)-induced rat model of MASLD. Rats were assigned to control, HFD, and PHF treatment groups (250&#xa0;mg/kg and 500&#xa0;mg/kg). The study assessed body weight, glucose homeostasis (fasting glucose, insulin sensitivity, HOMA-IR), lipid profiles, oxidative stress markers (MDA, GSH, antioxidant enzymes), and hepatic histopathology. RT-PCR was employed to analyse gene expression related to insulin signalling, lipid metabolism, and oxidative stress. PHF treatment significantly reduced body weight gain, normalised glucose metabolism, and improved insulin sensitivity in a dose-dependent manner. PHF mitigated HFD-induced dyslipidemia by reducing plasma and hepatic lipid levels. PHF also attenuated hepatic oxidative stress, restoring antioxidant enzyme activities. At the molecular level, PHF upregulated insulin signalling (IRS-1, PPARα), while downregulating lipogenic genes (FAS, SREBP1). Histopathological analysis revealed a dose-dependent reduction in hepatic steatosis, with near-complete restoration of hepatic architecture at 500&#xa0;mg/kg, as confirmed by the NAFLD Activity Score. In conclusion, the PHF effectively addresses both the first and second hits of the Two-Hit Hypothesis in MASLD, offering a holistic approach for managing this complex disease. These findings support PHF as a promising therapeutic candidate for MASLD, warranting further clinical exploration.</p>

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Polyherbal formulation mitigates high-fat diet-induced hepatic steatosis by targeting insulin resistance, hepatic lipid accumulation, and oxidative stress via modulation of the two-hit hypothesis

  • 期刊论文

  • 发表日期：

    2025年12月9日

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  • N. Chandrasekharnath,
  • A. Uma,
  • Y. V. Mahalakshmi

摘要

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a multifactorial condition linked to obesity, insulin resistance, dyslipidemia, and oxidative stress. While pharmacological interventions are limited, polyherbal formulations (PHF) offer a promising, multi-targeted approach for mitigating the pathogenesis of MASLD. The current study evaluated the therapeutic efficacy of a newly developed PHF comprising Vernonia amygdalina, Cissus quadrangularis, Eryngium foetidum, and Aristolochia indica in a high-fat diet (HFD)-induced rat model of MASLD. Rats were assigned to control, HFD, and PHF treatment groups (250 mg/kg and 500 mg/kg). The study assessed body weight, glucose homeostasis (fasting glucose, insulin sensitivity, HOMA-IR), lipid profiles, oxidative stress markers (MDA, GSH, antioxidant enzymes), and hepatic histopathology. RT-PCR was employed to analyse gene expression related to insulin signalling, lipid metabolism, and oxidative stress. PHF treatment significantly reduced body weight gain, normalised glucose metabolism, and improved insulin sensitivity in a dose-dependent manner. PHF mitigated HFD-induced dyslipidemia by reducing plasma and hepatic lipid levels. PHF also attenuated hepatic oxidative stress, restoring antioxidant enzyme activities. At the molecular level, PHF upregulated insulin signalling (IRS-1, PPARα), while downregulating lipogenic genes (FAS, SREBP1). Histopathological analysis revealed a dose-dependent reduction in hepatic steatosis, with near-complete restoration of hepatic architecture at 500 mg/kg, as confirmed by the NAFLD Activity Score. In conclusion, the PHF effectively addresses both the first and second hits of the Two-Hit Hypothesis in MASLD, offering a holistic approach for managing this complex disease. These findings support PHF as a promising therapeutic candidate for MASLD, warranting further clinical exploration.