Targeted protein degradation (TPD) is an emerging therapeutic strategy that leverages the natural protein degradation systems of cells to eliminate disease-associated proteins selectively. Unlike traditional small molecule inhibitors, which merely suppress protein activity, TPD degrades target proteins directly, offering a novel approach to addressing undruggable proteins. The two most extensively studied TPD technologies, proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs), utilize the ubiquitin–proteasome system to induce TPD. PROTACs function as bifunctional molecules that recruit an E3 ubiquitin ligase (E3 ligase) to a target protein, leading to its ubiquitination and subsequent degradation, while MGs enhance protein–protein interactions to facilitate ubiquitination and protein clearance. These approaches have shown promising therapeutic potential in treating cancer, neurodegenerative disorders, and autoimmune diseases, with several compounds currently undergoing clinical trials. Despite these advances, challenges such as limited bioavailability, pharmacokinetic constraints, and target selectivity remain obstacles to the widespread application of TPDbased therapies. Recent developments, including the discovery of novel E3 ligases, linker optimization, and AI-driven drug design, have addressed these limitations, paving the way for the next generation of precision-targeted therapeutics. This paper provides a comprehensive overview of the mechanisms, applications, and future directions of PROTACs and MGs in drug discovery, highlighting their potential to revolutionize modern targeted therapy.

Human dermal fibroblasts (HDFs) play a critical role in maintaining skin integrity and promoting tissue repair, but are highly susceptible to apoptosis under stress conditions such as nutrient deprivation. Adipose-derived stem cells (ADSCs) have emerged as a promising therapeutic option due to their regenerative potential and ability to secrete bioactive factors. In this study, we investigated the effect of ADSC-derived paracrine signaling on apoptosis in HDFs and explored the underlying molecular mechanisms. Using a Transwell co-culture system, we found that ADSCs significantly reduced apoptosis in HDFs subjected to low-serum stress, as confirmed by APOPercentage™ staining and the expression of apoptosis-related proteins. Among several soluble factors secreted by ADSCs, hepatocyte growth factor (HGF) exhibited the most pronounced time-dependent increase in culture supernatants. The anti- apoptotic effect of ADSCs was abolished by neutralizing antibodies against HGF, indicating a key role of this factor in mediating fibroblast survival. Further, HDFs were found to express the HGF receptor c-Met at both the mRNA and protein levels. Inhibition of c-Met signaling reversed the cytoprotective effect of ADSCs, suggesting that HGF functions through this receptor. Mechanistically, only the PI3K/AKT pathway—among the major survival pathways tested—was selectively activated in HDFs by ADSC co-culture. Pharmacological inhibition of PI3K/AKT signaling using LY294002 abolished the protective effect, while inhibition of ERK or p38 MAPK had no significant impact. These findings demonstrate that ADSC-derived HGF protects HDFs from stress-induced apoptosis primarily through activation of the c-Met–PI3K/ AKT pathway. This mechanistic insight may provide a basis for the development of stem cell– based therapies aimed at enhancing skin regeneration and fibroblast viability in degenerative or wound-healing contexts.

The success of artificial insemination (AI) in the swine industry relies on conserving the quality of boar sperm during liquid storage, as boar spermatozoa are prone to oxidative stress due to the high polyunsaturated fatty acid content and lack of antioxidant defenses. Sperm motility, viability, acrosome integrity, and DNA stability are all affected by the increases in reactive oxygen species (ROS) during storage, which lowers fertility. Ethyl pyruvate (EP), a stable derivative of pyruvate, has good antioxidant properties and has been shown to protect sperm quality in vivo. Its effects on boar sperm during in vitro preservation have not yet been investigated. This study investigated the effect of different concentrations of EP (0.1–1 mM) in Beltsville thawing solution at 17°C on the sperm quality parameters of boar spermatozoa over five days. Changes in sperm motility, viability, acrosome integrity, chromatin stability, and ROS were observed. The results showed that boar spermatozoa stored with 0.25–0.75 mM EP showed a significant increase in sperm motility, viability, acrosome integrity, and chromatin stability compared with the control (without EP) and 1 mM EP for 5 days. Compared to the control and 1 mM EP, ROS levels statistically decreased in sperm stored in 0.25–0.75 mM EP on both storage days 3 and 5. Our findings demonstrated that 0.25–0.75 mM of EP could enhance the boar sperm quality and mitigate the oxidative stress during liquid storage, thus revealing a strategy to improve fertility rates during AI in pig production.