Pharmaceutical mechanism of targeted protein degradation technology regulating protein homeostasis and its application in disease treatment

Proteostasis is the fundamental process by which cells maintain their normal functions. It involves maintaining the dynamic equilibrium of protein synthesis, folding, transport, and degradation. Disruption of proteostasis leads to the accumulation of misfolded proteins and a deficiency of functional proteins, triggering a pathological cascade—a hallmark of various diseases. Traditional drug development primarily focuses on inhibiting the activity of disease-causing proteins. However, many proteins are considered "undruggable" due to the absence of well-defined binding sites or functional redundancy. Recently, the targeted protein degradation (TPD) has provided a novel therapeutic strategy for traditionally undruggable targets. In this review, we systematically analyze how TPD overcomes the limitations of undruggable targets by remodeling the proteostatic network, covering the classification of protein degradation technologies, molecular mechanisms, and disease applications. Furthermore, we explore the clinical translation potential of TPD technologies, providing novel therapeutic strategies and theoretical frameworks for complex diseases.