Emerging perspectives in proteostasis: bridging mechanisms and therapeutics for human diseases.

Abstract

Cellular protein homeostasis, or proteostasis, underpins the integrity, adaptability, and survival of all cells by balancing protein synthesis, folding, trafficking, and degradation. This multilayered network is sustained by coordinated actions of molecular chaperones, the ubiquitin‒proteasome system, autophagy-lysosomal pathways, and organelle-specific quality control programs. When this equilibrium collapses, misfolded, aggregated, or damaged proteins accumulate, driving organelle dysfunction, maladaptive stress signaling, and disease progression. Disruption of proteostasis is now recognized as a unifying pathological hallmark linking neurodegenerative disorders, cancer, cardiovascular and metabolic diseases, and autoimmune conditions. This is particularly consequential in post-mitotic organs such as the heart and brain, which possess limited regenerative capacity and are exceptionally vulnerable to proteotoxic stress. Rapid advances now reveal proteostasis as a multicomponent, cross-compartmental, and dynamically adaptable system, rather than isolated pathways. We frame this complexity through the concept of proteostasis resilience, defined as the ability of cells and tissues to maintain proteome stability under stress, and use it to unify disease mechanisms with therapeutic opportunity. This review integrates mechanistic insights with translational advances, outlining how dysregulation of chaperones, autophagy-mitophagy, the ubiquitin‒proteasome system, and ER stress pathways drive human diseases, while highlighting emerging therapeutic platforms, from pharmacological chaperones and autophagy modulators to targeted protein degradation technologies, CRISPR screens, spatial biology, and AI-guided drug discovery. Together, this systems-level perspective positions proteostasis resilience as a foundational paradigm for understanding disease vulnerability and designing precision proteostasis-based therapies.