Integrated Multi-Omics and Network Pharmacology Reveal the Targeted Alleviation of MASLD by Litchi Pericarp Oligomeric Polyphenols via Quercetin

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global metabolic health burden, driving an urgent demand for safe, natural bioactive therapeutics derived from sustainable botanical sources. This study aimed to investigate the therapeutic efficacy and multi-target molecular mechanisms of litchi pericarp oligomeric polyphenols (LPPO) from Litchi chinensis Sonn. cv. Feizixiao against MASLD. A comprehensive multi-tiered pharmacological study design was conducted, integrating computational target prediction (network pharmacology and molecular docking) with in vitro cellular and in vivo animal disease models, combined with multi-omics profiling. Palmitate/oleate (FFA)-induced HepG2 cells and high-fat-diet (HFD)-fed C57BL/6J mice (JAX substrain) were treated with LPPO to evaluate hepatic steatosis, serum lipid profiles, oxidative stress parameters, and fecal lipid excretion. Integrated transcriptomics, metabolomics, network pharmacology, and molecular docking were conducted to pinpoint core bioactive constituents and validate key molecular targets and signaling pathways. LPPO markedly attenuated hepatic lipid accumulation, normalized serum lipid levels (TC, TG, and LDL-C), restored cellular redox balance (SOD and MDA), and promoted systemic lipid clearance via enhanced fecal excretion both in vitro and in vivo. Multi-omics integration identified quercetin as the principal bioactive metabolite driving LPPO-mediated metabolic reprogramming. Mechanistically, LPPO directly bound ALOX5 and downregulated ALOX12B to inhibit arachidonic acid-mediated inflammatory cascades, while suppressing NOS2/DUOX1 and upregulating MPV17L2 to alleviate oxidative/nitrosative stress. Additionally, quercetin downregulated the CD274 (PD-L1) checkpoint axis to reverse hepatic immunosuppression, alongside modulating GMPR, BCKDHA, and IDI1 to rebalance cellular energy allocation and lipid remodeling. LPPO exerts potent multi-target therapeutic effects against MASLD by alleviating lipotoxicity, oxidative stress, and inflammatory cascades. These findings elucidate the molecular basis of LPPO and highlight the potential of litchi pericarp waste as a high-value phytomedicinal resource.