Abstract

Breast cancer remains a global health challenge, with triple-negative breast cancer (TNBC) posing a particular therapeutic difficulty. Glycogen synthase 1 (GYS1), a key glycogen metabolic enzyme, is upregulated in various cancers under hypoxic stress and is associated with therapy resistance, but its functional role in BRCAs remains incompletely defined. Here, we identify a non-canonical, glycogen-independent mechanism by which GYS1 promotes breast cancer progression. We demonstrate that Gys1 knockout suppresses proliferation and migration of breast cancer cells in vitro and inhibits tumor growth in vivo. Crucially, neither ablation of other glycogen synthesis enzymes nor pharmacological inhibition of GYS1 recapitulates these effects, uncoupling the oncogenic role of GYS1 from its metabolic function. Mechanistically, GYS1 activates the canonical NF-κB pathway by promoting the ubiquitination and degradation of IκBα. GYS1 stabilizes the interaction between IκBα and its E3 ubiquitin ligase BTRC, facilitating IκBα proteasomal degradation and enabling nuclear translocation of NF-κB. Our findings establish GYS1 as a novel scaffold protein and an upstream regulator of NF-κB signaling independent of its enzymatic function, nominating it as a promising therapeutic target for breast cancer particularly for TNBC subtype that lacks effective treatment.