AdipoRon Suppresses Multiple Myeloma Proliferation Through AMPK-Mediated Metabolic Reprogramming and Apoptosis Induction

Multiple myeloma (MM) remains an incurable hematologic malignancy, necessitating novel therapeutic strategies. This study investigates the clinical significance of Adiponectin receptors and the anti-myeloma efficacy of their agonist, AdipoRon. Bioinformatic analysis of GEO datasets (GSE124489, GSE187009) revealed significant downregulation of ADIPOR1 and ADIPOR2 in MM patients. Low expression of ADIPOR1 correlated with poor prognosis. Functionally, AdipoRon exerted potent anti-proliferative effects on MM cell lines (U266, RPMI8226) in time- and dose-dependent manners. Mechanistic studies demonstrated that AdipoRon induced mitochondrial Apoptosis, evidenced by increased cleavage of PARP and Caspase-9, and triggered G0/G1 cell cycle arrest. At the signaling level, AdipoRon activated the AMPK pathway while concurrently suppressing Akt phosphorylation. The critical role of AMPK was confirmed through pharmacological approaches: the AMPK Activator AICAR mimicked AdipoRon's effects, whereas the AMPK Inhibitor Compound C partially reversed them. Further investigation identified Acetyl-CoA Carboxylase (ACC) as a key downstream effector, with ACC inhibition (TOFA) recapitulating AdipoRon's anti-MM effects. Specifically, AdipoRon preferentially suppressed ACC1 expression and subsequently downregulated CPT1A, indicating disruption of fatty acid metabolism. These findings establish that AdipoRon suppresses MM progression through AMPK-driven metabolic reprogramming and Apoptosis induction, positioning Adiponectin Receptor agonism as a promising therapeutic strategy for multiple myeloma.

AMPK signaling pathway; AdipoRon; acetyl‐CoA carboxylase (ACC); adiponectin receptor; multiple myeloma.