Otopetrin 1 in white adipose predicts the progression of cancer cachexia and protects against weight loss

Cancer cachexia is a major cause of mortality in cancer patients, and white adipose tissue (WAT) remodeling precedes weight loss. This study aimed to identify key genes driving cachexia progression and to target WAT loss for early intervention. Using Lewis lung carcinoma mouse models of pre-cachexia and cachexia, we systematically analyzed transcriptomic alterations in pathways and gene expression in WAT. Otopetrin 1 (OTOP1) was identified as a critical regulator of metabolic remodeling and inflammation. Overexpression of OTOP1 in adipocytes induced by tumor-conditioned medium attenuated lipolysis, promoted lipogenesis and exerted anti-inflammatory effects by inhibiting NF-κB signaling and activating PPARγ. In patients with cancer, OTOP1 expression in subcutaneous WAT was markedly reduced in cachexia and was associated with decreased BMI, albumin and hemoglobin, reflecting nutritional deterioration. Collectively, these findings demonstrate that OTOP1 regulates adipose metabolism and inflammation and may serve as a potential biomarker and therapeutic target for cancer cachexia.