AdipoR1-AMPK axis suppresses breast cancer across molecular subtypes via multimodal cell death pathways, including ferroptosis and apoptosis.

Adipokines secreted by adipocytes have emerged as critical modulators of cancer progression, particularly in obesity-associated malignancies. However, their therapeutic relevance and the tumor types responsive to adipokine pathways remain unclear. To identify adipokine-driven cancers and assess the therapeutic potential of adipokine signaling, we conducted a pan-cancer transcriptome analysis of the expression of various adipokine receptors in 31 tumor types. AdipoR1 was most frequently amplified and overexpressed in breast cancer across molecular subtypes. In the functional analysis, AdipoR1 stimulation using the agonist AdipoRon activated AMPK signaling, suppressed proliferation and migration, and induced apoptosis in both hormone receptor (HR)-positive (MCF7, T47D) and triple-negative (MDA-MB-231, MDA-MB-468) breast cancer cells. Notably, RNA-Seq analysis revealed that AdipoR1 stimulation upregulated ferroptosis-related genes, DDIT3, HMOX1, and IRE1α, and downregulated proliferation-related genes, estrogen receptor and TROP2, in breast cancer cell lines. Immunoblotting confirmed these changes at the protein level. AdipoR1 activation enhanced the efficacy of chemotherapeutic agents. In vivo, AdipoRon significantly reduced tumor growth and induced necrotic cell death. AdipoR1 activation exerts multimodal antitumor effects by engaging cell death and hormone receptor signaling. These findings establish AdipoR1 as a valuable therapeutic target in breast cancer and support further development of adipokine receptor-targeting therapies.