Authors
Jung Seung Nam, Sung Shin Ahn, Yeonoh Shin, Ariana Vargas-Castillo, Maya S Dixon, Pardis Ahmadi, Kathrin Schilling, Fereshteh Zandkarimi, Alex Chen, Nal Ae Yoon, Harrison Cullen, Yanping Sun, Thomas C Caffrey, Kelsey A Klute, Benjamin J Swanson, Jordan Lu, Samuel Pan, Yuxuan Chen, Shu Ichimiya, Geena Kim, Jeanine M Genkinger, Kazuki Sugahara, Michael D Kluger, Paul Grandgenett, Michael A Hollingsworth, Luke Berchowitz, Anthony W Ferrante, Lori M Zeltser, Sabrina Diano, Iok In Christine Chio
Published in
Nature cancer. Sep 22, 2026. Epub Sep 22, 2026.
Abstract
Adipose browning and atrophy are early events of cachexia, a lethal metabolic disorder affecting nearly half of the population with cancer. Here, using individual-derived specimens and mouse models, we identified an iron-dependent pathway that initiates adipose browning in both physiological and cachectic settings. Upon adrenergic 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 dimers in turn promote adipose browning by maintaining the reduced state of select substrates, including the catalytic subunit of protein kinase A. Remarkably, in mouse models, MsrA deletion impairs adipose browning, mitigates cachexia and prolongs the survival of tumor-bearing animals. Thus, as a key nexus of cancer-associated cachexia, the β3 adrenergic receptor-iron-MSRA axis is a promising target for clinical intervention.
PMID:
42773176
Bibliographic data and abstract were imported from PubMed on 23 Sep 2026.
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