Hypercholesterolemia is a major risk factor for cardiovascular disease, highlighting the urgent need for cholesterol-lowering therapies with novel mechanisms of action. Therefore, this study aims to employ high-throughput screening to characterize the structural features, target selectivity, and cholesterol-lowering potential of PG2, a structurally novel glycosylated piericidin isolated from deep-sea-derived actinomycetes. This structural motif distinguishes PG2 from other known piericidin analogues and confers its target selectivity. In vitro and in vivo studies demonstrated that PG2 significantly outperformed atorvastatin. Mechanistically, PG2 served as a direct and selective agonist of peroxisome proliferator-activated receptor δ (PPARδ). Activated PPARδ bound the promoter region of F-box and WD repeat domain-containing 7 (FBXW7), inducing its transcription. Subsequently, FBXW7 mediated the ubiquitin-dependent degradation of SREBP1, a key transcription regulator of cholesterol biosynthesis. FBXW7 silencing markedly reduced the protective effects of PPARδ activation against hypercholesterolemia. Collectively, these findings highlight a novel PPARδ-FBXW7-SREBP1 regulatory axis and support the potential of the marine-derived natural product PG2 as a therapeutic candidate for hypercholesterolemia.
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