IRS4 (insulin receptor substrate 4) is a scaffold protein that mediates signaling from growth factor receptors including insulin receptor, IGF1R, and FGFR1 to downstream effectors containing SH2 domains 1. The protein contains an N-terminal phosphotyrosine-binding (PTB) domain and pleckstrin homology (PH) domain that enable recruitment of signaling molecules 2. IRS4 promotes PI3K/AKT pathway activation and cell proliferation in response to growth factors 3. Notably, IRS4 lacks a SHP2-binding domain present in IRS1 and IRS2, enabling constitutive PI3K/AKT hyperactivation independent of insulin/IGF1 stimulation—a unique feature distinguishing it from other IRS family members 3. IRS4 plays roles in growth, reproduction, and glucose homeostasis [UniProt]. Pathologically, IRS4 is highly expressed in diverse cancers including breast, ovarian, gastric, and lung cancers 1. In ovarian cancer, FER tyrosine kinase phosphorylates IRS4 at Tyr779, enabling recruitment of the PI3K regulatory subunit PIK3R2 and driving tumor proliferation 2. IRS4 upregulation also occurs in benign tumors through chrX rearrangements 4. Clinically, IRS4 mutations cause X-linked congenital hypothyroidism 5, and IRS4 expression confers resistance to HER2-targeted breast cancer therapy 3.