An iron-regulated methionine redox axis governs adipose browning and cancer cachexia
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.
Authors
- Kelsey A. Klute (ORCID: https://orcid.org/0000-0002-4748-8520)
- Harrison B. Cullen (ORCID: https://orcid.org/0000-0003-1247-8186)
- Thomas C. Caffrey (ORCID: https://orcid.org/0000-0001-6707-8468)
- Ariana Vargas‐Castillo (ORCID: https://orcid.org/0000-0003-3239-6022)
- Nal Ae Yoon (ORCID: https://orcid.org/0000-0002-1223-4918)
- Jeanine M. Genkinger (ORCID: https://orcid.org/0000-0002-8438-0412)
- Fereshteh Zandkarimi (ORCID: https://orcid.org/0000-0001-8618-3669)
- Michael Anthony Hollingsworth (ORCID: https://orcid.org/0000-0002-5255-8888)
- Kazuki N. Sugahara (ORCID: https://orcid.org/0000-0002-4946-192X)
- Yeonoh Shin (ORCID: https://orcid.org/0000-0001-9718-2995)
- Anthony W. Ferrante (ORCID: https://orcid.org/0000-0001-9272-2593)
- Sabrina Diano (ORCID: https://orcid.org/0000-0002-7921-2617)
- Lori M. Zeltser (ORCID: https://orcid.org/0000-0002-4330-6240)
- Shu Ichimiya (ORCID: https://orcid.org/0000-0002-8184-615X)
- Kathrin Schilling (ORCID: https://orcid.org/0000-0003-4147-0298)
- Iok In Christine Chio (ORCID: https://orcid.org/0000-0002-3635-2679)
- Jordan Lu (ORCID: https://orcid.org/0000-0002-3380-1125)
- Luke Edwin Berchowitz (ORCID: https://orcid.org/0000-0002-3388-7723)
- Michael D. Kluger (ORCID: https://orcid.org/0000-0003-4311-078X)
- Jung Seung Nam (ORCID: https://orcid.org/0000-0001-8557-131X)
- Pardis Ahmadi (ORCID: https://orcid.org/0000-0003-3457-6588)
- Sung Shin Ahn (ORCID: https://orcid.org/0000-0002-1236-2143)
- Yuxuan Chen (ORCID: https://orcid.org/0000-0003-0727-1834)
- Paul Grandgenett
- Samuel Pan
- Benjamin J. Swanson
- Geena Kim
- Yanping Sun
- Maya S. Dixon
- Alex Chen (ORCID: https://orcid.org/0009-0001-3653-3023)
Publication Details
- Journal
- Nature Cancer
- Published
- 2026-09-22
- DOI
- https://doi.org/10.1038/s43018-026-01234-y
- Citations
- 1
- Primary Topic
- Cancer Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 3.14