Activation of PPARγ/FGF21 signaling axis with Puerarin reprograms tumor lipid metabolism, attenuating malignancy in colon cancer.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) stands as the third most prevalent malignancy and represents the second primary cause of cancer-associated deaths. Lipid metabolic reprogramming constitutes a cancer hallmark, distinguished by markedly elevated lipid synthesis and extensive lipid-droplet accumulation. Puerarin, an isoflavone from pueraria lobata, shows lipid metabolism regulation and anticancer activity. In this investigation, we examined whether puerarin could modulate lipid metabolism for the treatment of CRC and delved into the underlying mechanisms.

EXPERIMENTAL APPROACH: A network pharmacology-bioinformatics framework was developed to determine the potential targets of puerarin in CRC. For in vitro experiments, HCT-116, HCT-116/Oxa, SW480 and SW620 CRC cell models were chosen. We utilized western blotting (WB), quantitative real-time PCR (qRT-PCR), cell counting kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, Transwell, lipid-droplet immunofluorescence (IF) assay, RNA-sequencing analysis and flow cytometry analysis to examine the molecular mechanisms by which puerarin modulates lipid metabolism in CRC treatment. For in vivo experiments, we established two murine paradigms-a dextran sulfate sodium (DSS)-driven orthotopic CRC model and a subcutaneous xenograft model-and comprehensively evaluated the in vivo efficacy of puerarin against murine CRC, together with its underlying mechanisms, by colonoscopy, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (H&E), immunohistochemical (IHC), IF and WB analyses.

KEY

RESULTS

Our findings established that peroxisome proliferator-activated receptor gamma (PPARγ) as a bona fide target through which puerarin rewireed lipid metabolism in CRC. Loss of PPARγ was tightly linked to aggressive disease progression, whereas puerarin-by activating PPARγ-boosted downstream fibroblast growth factor 21 (FGF21) expression, suppressed the phosphoinositide 3-Kinase (PI3K)/ protein kinase B (AKT)/ mechanistic target of rapamycin (mTOR) axis, and thereby disrupted tumor lipogenesis. This signaling rewiring attenuated malignant growth and chemoresistance both in vitro and in vivo.

CONCLUSION AND IMPLICATIONS: Puerarin halted the malignant progression of CRC by reprogramming tumor lipid metabolism. Puerarin thus hold promise as a clinically deployable lipid-centric agent that could synergistically potentiate conventional anticancer drugs.