Tumor-derived miR-203a-3p potentiates muscle wasting by inducing muscle ferroptosis in pancreatic cancer

Abstract

Pancreatic cancer (PC) cachexia, characterized by profound muscle wasting and systemic inflammation, remains a formidable clinical challenge due to its multifactorial nature and complex molecular underpinnings. This study delves into the intricate interplay between microRNA (miRNA) dysregulation and ferroptosis, a form of iron-dependent cell death, in PC cachexia. Specifically, we identified tumor-derived miR-203a-3p as a pivotal miRNA that promotes muscle atrophy by upregulating muscle ferroptosis. Our findings revealed that miR-203a-3p targets zinc finger E-box binding homeobox 1 (ZEB1), subsequently enhancing the expression of the iron transporter solute carrier family 11 member 2 (SLC11A2), thereby facilitating ferroptosis-associated skeletal muscle cell death. Through in vivo experiments using a PC cachexic mouse model, we demonstrated that inhibiting ferroptosis effectively attenuated muscle wasting, highlighting its critical role in the pathogenesis of PC cachexia. These results provide a molecular framework elucidating how miRNA regulation and ferroptosis converge to drive muscle atrophy, offering novel therapeutic avenues for mitigating cachexia in PC patients. By targeting these pathways, we aim to improve muscle preservation and overall survival in this devastating disease.