CircAMOTL1 promotes adipose lipolysis and browning in cancer cachexia through miR-211-5p-mediated TET2 activation

Cancer cachexia is characterized by profound adipose tissue loss and metabolic remodeling, yet the regulatory mechanisms driving adipocyte dysfunction remain incompletely understood. Through whole-transcriptome sequencing of human subcutaneous adipose tissue, we identified circAMOTL1 as one of the most significantly upregulated circRNAs in patients with cachexia. circAMOTL1 expression positively correlated with weightloss severity and demonstrated strong diagnostic performance for cachexia. Functional studies revealed that circAMOTL1 promotes lipolysis and white adipose browning in adipocytes as evidenced by increased expression of ATGL, HSL, UCP1, and PGC-1α, elevated free fatty acid release, and enhanced mitochondrial content. Silencing circAMOTL1 produced the opposite phenotype. Mechanistically, circAMOTL1 localized predominantly in the cytoplasm and acted as a molecular sponge for miR-211-5p, thereby relieving miR-211-5p-mediated repression of TET2. Luciferase reporter, RIP, and FISH assays confirmed the circAMOTL1/miR-211-5p/TET2 regulatory interaction. Gain- and loss-of-function experiments demonstrated that TET2 is essential for circAMOTL1-induced lipolysis and thermogenic remodeling. In vivo, adipose-targeted recombinant AAV overexpression of circAMOTL1 in a C26 tumor-bearing mouse model induced adipose wasting and upregulated lipolytic and browning markers, phenocopying cachexia-associated adipose remodeling. These findings identify circAMOTL1 as a critical regulator of adipocyte metabolism in cancer cachexia. By modulating the circAMOTL1/miR-211-5p/TET2 axis, it drives lipolysis and thermogenic reprogramming of white adipose tissue. circAMOTL1 therefore represents a promising biomarker and a potential therapeutic target for preventing or attenuating cachexia-associated adipose tissue loss.