Abstract A005: An Iron-regulated Signalling Pathway Controls Adipose Browning and Cancer Cachexia

Abstract Browning and atrophy of white adipose tissue (WAT) are early events of cachexia, a lethal metabolic disorder affecting nearly half of cancer patients, including those with pancreatic ductal adenocarcinoma (PDA). Using patient-derived specimens and PDA mouse models, we identified an iron-dependent signalling pathway that initiates adipose browning in both physiological and cachectic settings. Upon sympathetic stimulation of adipocytes, an influx of iron induces the activity of methionine sulfoxide reductase A (MSRA), an enzyme that reverses the oxidation of proteinaceous methionine residues. Mechanistically, iron coordination by the conserved iron-binding EXXH motif of two MSRA polypeptides serves to dimerize, stabilize, and elevate its reductase activity. Iron-bound MSRA in turn promotes adipose browning by maintaining the reduced state of select substrates, including a conserved methionine (Met71) in the ATP-binding site of Protein Kinase A (PKA). Remarkably, in mouse models of PDA, MsrA deletion impairs WAT browning, significantly mitigates cachexia, and improves the overall survival of tumour-bearing animals. By establishing the b3AR-iron-MSRA-PKA axis as a key nexus of cancer-associated cachexia, this study opens new perspectives for clinical intervention. Citation Format: JungSeung Nam, Sung Shin Ahn, Yeonoh Shin, Ariana Vargas-Castillo, Maya Dixon, Pardis Ahmadi, Kathrin Schilling, Fereshteh Zandkarimi, Alex Chen, Nal Ae Yoon, Harrison Cullen, Yanping Sun, Thomas Caffrey, Kelsey Klute, Benjamin Swanson, Jordan Lu, Samuel Pan, Yuxuan Chen, Shu Ichimiya, Geena Kim, Jeanine Genkinger, Kazuki Sugahara, Michael Kluger, Paul Grandgenett, Michael Hollingsworth, Luke Berchowitz, Anthony Ferrante Jr., Sabrina Diano, Christine Chio. {Abstract title} [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A005.