NF-κB signaling drives rapid skeletal muscle atrophy in patients with breast cancer: The cost of fighting cancer with chemotherapy

Skeletal muscle wasting is a critical clinical challenge in patients with breast cancer treated with chemotherapy, given its correlation with increased mortality risk and decreased therapeutic efficacy. However, the mechanisms underlying this side effect remain poorly understood, slowing the development of effective preventive strategies. Here, we conducted a translational study using an innovative multimodal experimental design to comprehensively investigate the mechanisms driving chemotherapy-induced muscle atrophy. We analyzed 72 samples from 36 patients with breast cancer across four experimental groups at various time points during chemotherapy, complemented by in vitro experiments. Through histological, transcriptomic, targeted protein expression, and activity-based analyses, we identified NF-κB signaling and the subsequent upregulation of the ubiquitin–proteasome system as drivers of chemotherapy-induced muscle atrophy. In vitro, sulfasalazine effectively mitigated the imbalance in protein turnover and fully prevented muscle atrophy, offering promising perspectives for clinical translation and improving patient prognosis.