Frontier Technologies And News

PROTAC (proteolysis-targeting chimera) is a technique that uses a class of small molecules to target specific proteins for degradation. The small molecules are heterobifunctional, consisting of two protein binding parts joined by a linker. One part of the molecule binds a protein of interest (POI), while the other part binds to an E3 ubiquitin ligase, bringing the E3 ligase close to the POI for ubiquitination coupled protein degradation. The first successful PROTAC study used the chimeric PROTAC-1 molecule to recruit the β-TrCP E3 ligase to dictate the ubiquitination and degradation of MetAP2. There are over 600 E3 ligases, and only a few have been successfully developed by PROTAC to degrade target proteins. Among them, CRBN- and VHL-based PROTAC have been extensively explored and successfully applied for multiple disease treatments. The E3 ligased MDM2, c-IAP, and XIAP are fruitful in using PROTAC strategy for cancer treatment. PROTAC design using the KEAP1 E3 ligase has been developed for degradation of BRD3, BRD4, and Tau. KEAP1 is another promising member of the PROTAC team.

Zhang Yao et al.'s article "Single-Cell Analysis of Chemotherapy-induced Remodeling Reveals CD276-driven Basal-like Chemoresistance in Pancreatic Cancer," published in the 2026 issue of Gastroenterology, leverages high-precision multi-omics technology to focus on chemotherapy-induced dynamic remodeling of PDAC tumor cells and microenvironment, deeply excavating the core molecular mechanisms of chemotherapy resistance, aiming to solve the dilemma of PDAC chemotherapy resistance and provide new targets and theoretical support for clinical precision targeted therapy.

Published in *Advanced Science*, this research was completed by the teams of Min Zhou and Danni Zhong from the First Affiliated Hospital, Zhejiang University School of Medicine. They constructed a colon-targeted CV@PA-gel synergistic platform and clarified its mechanism for intervening IBD gut-brain comorbidity: CV@PA-gel treatment, a novel, safe and effective intervention, can maintain intestinal barrier integrity and reduce gut microbiota translocation, further block microglia-induced A1 astrocyte transformation, and ultimately alleviate DSS-induced depressive-like behaviors and cognitive dysfunction.

Redox homeostasis denotes the maintenance of the balance between oxidants and antioxidants. Although excessive oxidant production causes oxidative damage to cellular biomolecules and results in oxidative distress, lack of adequate oxidant levels impairs crucial signalling processes and results in reductive distress.

Combining the unique molecular structure of SNAP25—a large intrinsically disordered linker region between the two SNARE motifs, with cysteines in the linker region that can undergo palmitoylation modification—and previous experimental conclusions that Syntaxin-1 enhances SNAP25 palmitoylation, the authors proposed a complete scientific hypothesis: SNAP25 undergoes liquid-liquid phase separation through its disordered linker region, with palmitoylation modification and Syntaxin-1 jointly regulating condensate formation. The droplets produced by phase separation can recruit all SNARE components to promote ternary complex assembly. DEE pathogenic mutations disrupt phase separation and block the membrane fusion pathway, thereby completely filling the research gap in the mechanism of SNARE protein aggregation.

The Bcl-2 family consists of a number of evolutionarily conserved proteins containing Bcl-2 homology domains (BH) that regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Four BH domains have been identified (BH1-4) that mediate protein interactions. The family can be separated into three groups based upon function and sequence homology: pro-survival members include Bcl-2, Bcl-xL, Mcl-1, A1 and Bcl-w; pro-apoptotic proteins include Bax, Bak and Bok; and "BH3 only" proteins Bad, Bik, Bid, Puma, Bim, Bmf, Noxa and Hrk. Interactions between death-promoting and death-suppressing Bcl-2 family members has led to a rheostat model in which the ratio of pro-apoptotic and anti-apoptotic proteins controls cell fate. Thus, pro-survival members exert their behavior by binding to and antagonizing death-promoting members. In general, the "BH3-only members" can bind to and antagonize the pro-survival proteins leading to increased apoptosis. While some redundancy of this system likely exists, tissue specificity, transcriptional and post-translational regulation of many of these family members can account for distinct physiological roles.

Apoptosis is a regulated physiological process leading to cell death. Caspases, a family of cysteine acid proteases, are central regulators of apoptosis. Initiator caspases (including 2, 8, 9, 10 and 12) are closely coupled to proapoptotic signals, which include the FasL, TNF-α, and DNA damage. Once activated, these caspases cleave and activate downstream effector caspases (including 3, 6 and 7), which in turn cleave cytoskeletal and nuclear proteins like PARP, α-fodrin, DFF and lamin A, and induce apoptosis.

Pro-Apoptosis Bcl-2 Family Antibody The Bcl-2 family consists of a number of evolutionarily conserved proteins containing Bcl-2 homology domains (BH) that regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Four BH domains have been identified (BH1-4) that mediate protein interactions. The family can be separated into three groups based upon function and sequence homology: pro-survival members include Bcl-2, Bcl-xL, Mcl-1, A1 and Bcl-w; pro-apoptotic proteins include Bax, Bak and Bok; and "BH3 only" proteins Bad, Bik, Bid, Puma, Bim, Bmf, Noxa and Hrk. Interactions between death-promoting and death-suppressing Bcl-2 family members has led to a rheostat model in which the ratio of pro-apoptotic and anti-apoptotic proteins controls cell fate (4). Thus, pro-survival members exert their behavior by binding to and antagonizing death-promoting members. In general, the "BH3-only members" can bind to and antagonize the pro-survival proteins leading to increased apoptosis. While some redundancy of this system likely exists, tissue specificity, transcriptional and post-translational regulation of many of these family members can account for distinct physiological roles.

The synapse is the unit of information transfer in the brain between neurons. Synaptic transfer is initiated by action potential-initiated synaptic vesicles fusion at the presynaptic terminal to release neurotransmitters. The basic molecular machinery that drives all membrane fusion events in all cells include N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that form a trans-ternary complex between to-be-fused membranes. The zippering up of SNARE proteins provides the energy required for membrane fusion. At the synapse, the SNARE proteins include 25 kDa synaptosome-associated protein (SNAP25), syntaxin 1A (STX1A), and vesicle-associated membrane protein 2 (VAMP2, also called synaptobrevin). Neurotransmitter release, however, is a highly regulated process that occurs in response to action potential-initiated Ca2+-influx. Regulation of synaptic vesicle fusion is mediated by SNARE-binding proteins like complexin and the Ca2+-associated vesicle protein, synaptotagmin-1, that cooperatively function to initiate Ca2+-induced synaptic vesicle fusion. The synaptic vesicle cycle represents a cycle of events that prime the synaptic vesicle before fusion and retrieve fused membrane after full fusion. Synaptic vesicle-associated proteins like synaptophysin and synapsin-1, as well as target membrane proteins like Munc18-1, play a complex role in priming synaptic vesicles to be fusion competent.

The key to cell lysis lies in balancing violence and gentleness, ensuring protein integrity, and providing a reliable foundation for downstream analysis.