Adipocyte-derived FABP4 Drives Pancreatic Cancer Radioresistance via FABP4- eIF3a Axis

Abstract Background Radiotherapy is a common treatment modality for patients with locally advanced or metastatic pancreatic cancer, but the therapeutic efficacy is constrained by intrinsic radioresistance. The tumor microenvironment, particularly peritumoral adipose tissue, plays a critical yet poorly understood role in modulating therapeutic responses. Methods Peritumoral adipose tissue distribution in pancreatic cancer was assessed by H&E staining. The effects of adipocytes on cancer cell radiosensitivity were evaluated using a co-culture system combined with colony formation, alkaline comet, and flow cytometry assays. Energy metabolism, lipid accumulation, and fatty acid transporter levels in co-cultured cancer cells were examined by Seahorse analysis, BODIPY staining, real-time PCR, and immunofluorescence. The role of FABP4 in adipocyte-mediated radiosensitivity regulation was tested using FABP4-knockout 3T3-L1 cells, exogenous FABP4 protein, and a FABP4 inhibitor. FABP4-overexpressing cancer cells and nude mouse xenografts were used to determine the effects of FABP4 on radiosensitivity. Underlying mechanisms were explored and validated by Co-IP, LC-MS/MS, RIP, and other approaches. Results The results of the pathology showed that the pancreatic cancer was surrounded by peripancreatic adipose tissue. Co-culture with adipocytes significantly enhancing clonogenic survival of pancreatic cancer cells while attenuated radiation-induced DNA damage, apoptosis, and G2/M arrest, an effect mediated by FABP4. Genetic ablation of FABP4 in adipocytes abolished this radioprotection, whereas exogenous FABP4 supplementation or its overexpression recapitulated radioresistance both in vitro and in vivo. Proteomic screening identified eIF3a as the predominant FABP4-interacting protein. Functional validation demonstrated that eIF3a knockdown abrogated the FABP4-enhanced radioresistance, confirming its essential role in this process. EIF3a knockdown increased KU80 and MRE11 expression and promoted radioresistance, whereas FABP4 suppressed KU80 and MRE11 expression by enhancing eIF3a–mRNA binding. Conclusions This study identify adipocyte‑derived FABP4 as a pivotal regulator of pancreatic cancer radiosensitivity and unveil the FABP4–eIF3a axis as a potential therapeutic target for radiosensitization.