Stress-inducible circSCLT1 scaffolds HNRNPA1/CSDE1 to amplify IL1B/NF-κB signaling in TNBC via mRNA stabilization, suppressor degradation, and stress granule shielding.

Triple-negative breast cancer (TNBC) exhibits robust self-regulatory mechanisms against harsh microenvironmental stress, yet the precise molecular drivers remain elusive. Here, we identified circSCLT1 as a novel circular RNA with energy stress-responsive properties. Systematic in vitro and in vivo assays demonstrated that circSCLT1 promotes TNBC metastasis and radioresistance. Mechanistically, energy stress triggers HNRNPA1-dependent circSCLT1 biogenesis. Cytoplasmic circSCLT1 scaffolds a ternary complex with HNRNPA1 and CSDE1, blocking HNRNPA1 nuclear translocation and stabilizing IL1B via binding to its coding sequence (CDS). Additionally, the circSCLT1-containing complex displaces the E3 ubiquitin ligase TRIM25 from CSDE1 and redirects it toward TIAL1, thereby inducing K48-linked polyubiquitination and proteasomal degradation of TIAL1. Furthermore, circSCLT1 suppresses arginine dimethylation of HNRNPA1 by reinforcing the binding between CSDE1 and HNRNPA1, which in turn facilitates stress granule (SG) assembly under severe energy stress. These circSCLT1/HNRNPA1/CSDE1-containing SGs shield IL1B from autophagy-mediated degradation. Collectively, these actions amplify IL1B/NF-κB signaling, sustaining pro-survival networks that drive metastasis and radioresistance. Importantly, pharmacological inhibition of IL-1β secretion using disulfiram (DSF) synergizes with circSCLT1 silencing to markedly suppress tumor progression and extend survival in preclinical TNBC models. Our findings elucidate the oncogenic role of circSCLT1 in TNBC and underscore its potential as a novel therapeutic target, providing a rationale for combining IL-1β inhibition with circSCLT1-targeted therapy.