Deciphering the hepatoprotective mechanism of Sarcopyramis nepalensis wall against non-alcoholic fatty liver disease by network pharmacology and experimental validation

Non-alcoholic fatty liver disease (NAFLD) represents a widespread hepatic condition marked by excessive lipid accumulation. Sarcopyramis nepalensis Wall (S. nepalensis), a hepatoprotective traditional Chinese herbal medicine, has unclear pharmacodynamics and mechanisms against NAFLD. This study integrated UHPLC-Q Exactive Orbitrap-HRMS analysis, network pharmacology, molecular docking, and in vivo models to elucidate the therapeutic role of S. nepalensis in high-fructose diet-induced NAFLD. Analysis identified 50 bioactive constituents and 224 potential targets, with enrichment in insulin resistance, lipid metabolism, and PI3K/Akt signaling. Molecular docking results confirmed stable binding between the core components and key targets. Experimental validation in mice demonstrated that S. nepalensis decreased liver fat accumulation and liver damage, suppressed IL-6, IL-1β, and TNF-α expression, and upregulated the levels of InsR, HIF-1α, p-PI3K/PI3K, and p-Akt/Akt. Collectively, our findings demonstrate that S. nepalensis protects against NAFLD by activating the InsR/PI3K/Akt/HIF-1α pathway, thereby ameliorating insulin resistance, fat accumulation, and inflammation.