Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations

Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comprehensive and multidimensional analysis of protein folding biology, tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics. We explore the historical progression of protein folding research, including landmark discoveries of secondary structure, chaperone biology, and energy landscape theory. We detail the roles of key molecular chaperones across cytosolic, mitochondrial, and endoplasmic reticulum compartments, emphasizing their collaborative actions in protein folding and quality control. We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences, paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity. We then examine therapeutic innovations targeting proteostasis, including chaperone modulators, proteostasis pathway inhibitors, and emerging strategies to increase proteome resilience. By consolidating insights at the molecular, cellular, and systems levels, this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.