An iron-regulated methionine redox axis governs adipose browning and cancer cachexia
Menée à l'aide de modèles murins et d'échantillons tissulaires d'origine humaine, cette étude met en évidence un mécanisme par lequel le processus d'oxydo-réduction impliquant la méthionine et régulé par le fer favorise le brunissement du tissu adipeux et la cachexie liée au cancer, puis démontre que cet axe moléculaire constitue une cible thérapeutique prometteuse
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.
Nature Cancer , article en libre accès, 2026