Adipocytes Promote Cisplatin Resistance through Secreting A1BG and Regulating NAMPT/PARP1 Axis-Mediated DNA Repair in Osteosarcoma.

Obesity is increasingly recognized as a negative prognostic factor for cancers, including osteosarcoma. However, the mechanisms linking obesity to chemoresistance in osteosarcoma remain unclear. This study found obesity is significantly associated with poor responses to cisplatin-based chemotherapy in osteosarcoma patients. In vitro, adipocyte-conditioned medium (Adi-CM) induced cisplatin resistance, while peritumoral adipocytes and diet-induced obesity (DIO) reduce the cisplatin efficacy in vivo. Mechanistically, Adi-CM enhanced DNA repair by the PARP1/ATM pathway activation. Proteomic analysis identified A1BG, a secreted protein upregulated in adipocytes from chemoresistant patients, as a key mediator of this effect. A1BG depletion in adipocytes restored cisplatin sensitivity, whereas recombinant A1BG enhanced resistance and promoted DNA repair. Further investigation revealed a direct interaction between A1BG and NAMPT, leading to the stabilization of NAMPT and an increased NAD(+) production. This enhanced PARP1 activity and subsequent DNA repair. Importantly, pharmacological inhibition of NAMPT and PARP1 using FK886 and Olaparib, respectively, reversed Adi-CM-induced cisplatin resistance and restored cisplatin sensitivity in osteosarcoma cells, DIO mouse models, and patient-derived organoids. A novel link between obesity and cisplatin resistance in osteosarcoma is established, highlighting the A1BG/NAMPT/PARP1 axis as a critical driver. Targeting this axis may represent a promising therapeutic strategy for overcoming obesity-associated chemoresistance in osteosarcoma.