Reprogramming muscle proteostasis in cancer cachexia: Transcriptional mechanisms and therapeutic opportunities

Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting that diminishes quality of life, limits responses to anticancer therapies, and increases mortality. Although excessive protein degradation has traditionally been viewed as a primary driver of muscle loss, cachectic muscle undergoes broader disruption of proteostasis involving protein turnover, organelle quality control, stress adaptation, metabolism, and regenerative capacity. Accumulating evidence suggests that diverse tumor- and host-derived signals converge on interconnected transcriptional networks that coordinate these processes. Rather than functioning independently, transcription factors integrate inflammatory, metabolic, hormonal, and cellular-stress signals to generate catabolic, stress-responsive, anabolic, and regenerative programs whose effects vary with disease stage and cellular context. Importantly, these transcriptional responses are not uniformly pathological but can represent causal, adaptive, or compensatory programs. Epigenetic, post-transcriptional, and post-translational mechanisms provide additional layers that shape the activation and magnitude of these transcriptional programs. Emerging single-cell and multi-omic approaches have further revealed myofiber- and cell-specific regulatory networks underlying the heterogeneous response of skeletal muscle to tumor growth. In this review, we argue that transcriptional reprogramming represents a central integrative mechanism through which diverse catabolic signals remodel skeletal muscle proteostasis, and we examine how network-level regulation contributes to muscle adaptation and wasting in cancer cachexia. Defining which regulatory programs are causal, compensatory, or maladaptive may reveal more precise biomarkers and therapeutic targets for preserving skeletal muscle mass and function in patients with cachectic cancer.