Jinwei Zhang

Virtual screening (VS) stands as a cornerstone of early‐stage drug discovery, yet long‐standing hurdles—including prohibitive computational cost and limited cross‐target generalization—have long restricted its genome‐wide application, especially with the rapid expansion of AlphaFold‐predicted protein structures. Over the past 2 years, contrastive learning has emerged as a genuinely transformative paradigm, with DrugCLIP as a landmark implementation that reimagines virtual screening as fast embedding‐based dense retrieval. This commentary offers a balanced overview of DrugCLIP's core innovations: its contrastive framework that aligns protein pocket and small‐molecule representations, paired with GenPack for targeted pocket refinement of predicted structures. We synthesize recent benchmark results validating its performance relative to molecular docking and machine‐learning baselines, recap wet‐lab success stories across psychiatric and cancer‐associated targets, and assess the real‐world impact of the resulting GenomeScreenDB resource. We further place DrugCLIP in context with contemporary computational tools including RosettaVS, Deep Docking, and AF2‐RAVE, highlight unresolved challenges such as translating binding predictions into functional activity and screening against tough PPI targets, and outline actionable avenues for future development. Taken together, this work illustrates how contrastive learning is quietly reshaping informatics‐driven drug discovery and opening the undrugged genome to systematic exploration.

On August 8, 2025, Arvinas and Pfizer announced that the FDA had accepted the NDA for vepdegestrant (ARV-471, PF-07850327) for the treatment of patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) and ESR1-mutated advanced or metastatic breast cancer who have previously received endocrine-based therapy. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of June 5, 2026. Vepdegestrant, a first-in-class oral PROTAC ® estrogen receptor (ER) degrader, is a heterobifunctional molecule. It consists of an ER-binding moiety derived from lasofoxifene, a cereblon (CRBN)-targeting ligand based on lenalidomide, and a rigid N-containing heterocycle linker. This structure enables selective recruitment of the E3 ubiquitin ligase CRBN to ER, driving ubiquitination and proteasomal degradation.

Tendinopathy is a chronic and degenerative tendon disorder with limited therapeutic options. Recent insights into the cellular pathogenesis of tendinopathy have revealed that tendon-derived stem cells may aberrantly differentiate into chondrocytes under micro-injury-induced endoplasmic reticulum stress. In a recent study published by Tu et al in the World Journal of Stem Cells , thymoquinone - a bioactive compound from Nigella sativa - was demonstrated to inhibit the chondrogenic differentiation of tendon-derived stem cells both in vitro and in vivo , primarily through attenuation of the protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic initiation factor 2/activating transcription factor 4/CCAAT/enhancer-binding protein homologous protein pathway. This article evaluates the significance of these findings within the broader field of tendon biology, highlights methodological strengths, and discusses future research directions for translating thymoquinone into a potential therapy for tendinopathy.

Objective: This study was undertaken to characterize the functional impact of novel SLC12A5 variants in two unrelated patients with early onset developmental and epileptic encephalopathy (DEE) and to investigate the mechanisms underlying KCC2 dysfunction. Methods: Clinical, genetic, and functional analyses were performed in two patients (Cases A and B) with DEE. SLC12A5 encodes two KCC2 splice isoforms (KCC2a and KCC2b). Functional effects of the identified variants on KCC2b ion transport, phosphorylation, mRNA processing, and KCC2‐dependent synaptogenesis were assessed using in vitro assays in heterologous expression systems and primary neurons, supported by in silico structural modeling. Results: Both patients developed severe neonatal onset DEE characterized by developmental delay, axial hypotonia, extrapyramidal features, and bilateral migratory seizures within 24 h of birth. Both cases resulted in early mortality (Case A at 9 years; Case B at 6 months). Sequencing revealed distinct biallelic compound heterozygous SLC12A5 variants in both individuals, each inherited from one unaffected parent. Functional analyses demonstrated that in Case A, one variant markedly reduced KCC2‐mediated ion transport, whereas the second variant preserved transport activity but exhibited an altered phosphorylation profile at Ser940, located on the intracellular C ‐terminal region. This variant also disrupted wild‐type (WT) KCC2‐dependent excitatory synapse formation in immature rat hippocampal neurons. In Case B, one variant disrupted normal mRNA transcript processing consistent with loss of expression, and the second variant exhibited reduced ion transport activity. Significance: These data demonstrate that SLC12A5 ‐related DEE can result from combined impairment of KCC2‐dependent chloride homeostasis and disruption of chloride‐independent KCC2 functions critical for early neuronal development. This work expands the mutational and mechanistic spectrum of SLC12A5 ‐DEE and highlights the importance of KCC2 regulatory roles in early brain development, providing new knowledge and tools for basic research and potential avenues for targeted precision therapies.

Sulfur-containing functional motifs are embedded in roughly 25% of all FDA-approved small-molecule drugs, yet direct and practical methods for converting abundant carbonyl compounds into their sulfur-bearing analogs have long been constrained by toxic reagents, lengthy multi-step procedures, and narrow functional group compatibility. A landmark recent breakthrough has established a concise two-step Carbonyl- to-Sulfur (CO-to-S) skeletal transformation that relies on sequential C-C bond cleavage driven by a Nitrogen-Assisted Homolytic Activation (NAHA) reagent, paired with a Tosyl Disulfide (Ts-S-Ts) mediator under mild radical conditions (Zhang and Dong, Science, 2025). This perspective offers an in-depth dissection of the mechanistic elegance underpinning this strategy, with a sharp focus on its transformative roles in late-stage derivatization of drug candidates, rapid diversification of molecular scaffolds, and precise optimization of metabolic profiles. By situating this approach within the broader landscape of sulfur-centered chemistry in modern drug design, we critically evaluate its distinct advantages over conventional thiolation methods, address current limitations in stereochemical control and substrate scope, and outline promising future directions for enantioselective variants and applications in bioconjugation chemistry.

Exploration of Marine Microorganisms for Sustainable Biotechnology-Bridging Discovery,The ocean, covering over 70% of Earth's surface, harbors an estimated 10 29 microbial cells that form the foundation of marine ecosystems and a largely untapped reservoir of biotechnological potential.As global demands for sustainable solutions intensify-from environmental remediation to novel bioproduct development-marine microorganisms have emerged as pivotal players, offering unique metabolic pathways, enzymes, and bioactive compounds shaped by millions of years of adaptation to extreme and diverse habitats. This special issue, "Exploration of Marine Microorganisms for Sustainable Biotechnology," aims to showcase cutting-edge research that unlocks this potential while upholding the principles of ecological sustainability and responsible resource utilization.Sustainable biotechnology relying on marine microbes addresses two critical global imperatives: harnessing nature's innovation for human needs and safeguarding the marine environment that sustains these resources. Marine microbial communities, from shallow coastal waters to the hadal zone (6,000-11,000 m depth), have evolved specialized metabolic capabilities to thrive in oligotrophic, high-pressure, low-temperature, or pollutant-rich environments. These adaptations translate into unique biocatalysts for biodegradation, novel secondary metabolites for therapeutics and 1 cosmetics, and efficient biosynthetic pathways for applications. 2 Yet, realizing this potential is hampered by inherent challenges. The "great plate count anomaly" 3 leaves over 99% of marine microbes unculturable under conventional laboratory conditions, limiting 4 direct access to their metabolic diversity. Logistical hurdles in deep-sea sampling and analysis, 5 coupled with the need to balance resource exploitation ecosystem preservation, further 6 complicate progress. Fortunately, recent technological advances-including metagenomic sequencing, 7 single-cell genomics, synthetic biology, and sustainable cultivation systems-have begun to 8 overcome these barriers, enabling unprecedented insights into microbial diversity, function, and 9 application that lay the groundwork for the research featured in this special issue. 10Building on these technological breakthroughs, this special issue brings together 5 impactful 11 publications (4 research articles and 1 comprehensive review) that align with the core themes of 12 marine microbial exploration, sustainable utilization, and biotechnological innovation. Collectively, 13 these works advance our understanding of marine microbial biology while providing practical 14 solutions for industrial and environmental challenges, directly addressing the imperatives and 15 (HMW) PAHs-persistent organic pollutants (POPs) with severe ecological and human health 17 impacts. The strain exhibits robust degradation efficiency under low-temperature and high-pressure 18 conditions, mirroring its native habitat, showcasing how microbial adaptations to extreme 19 environments can be harnessed for bioremediation. 20Complementing this work, Sardar identifies a marine Metabacillus niabensis strain capable of 21 degrading polyethylene (PE)-one of the most abundant and recalcitrant plastics in marine 22 environments. The study characterizes the biodegradation pathway and key enzymes involved, 23 providing evidence for microbial adaptation to plastic pollution in marine ecosystems. Together, these 24 two studies align with emerging research highlighting marine microbes as critical agents for 25 environmental self-repair, offering practical strains and mechanisms for developing sustainable 26 bioremediation technologies that address the imperative of safeguarding the marine environment 27 while solving human-induced pollution challenges. 28The publications in this special issue represent significant strides in marine microbial sustainable 29 biotechnology, but several frontiers remain to be explored to fully realize the potential outlined in the 30 thematic landscape. First, advancing sustainable cultivation techniques for unculturable microbes-31 such as microfluidic-based single-cell cultivation and in situ simulation of marine habitats-will 32 expand access to microbial diversity beyond what current culture-independent methods can achieve. 33Second, integrating synthetic biology with genome mining (as demonstrated in Yuan et al.'s 1 production of high-value compounds, addressing the industrial application gap. Third, conducting 1 comprehensive life cycle assessments (LCAs) of marine microbial bioprocesses-from sampling to 2 production-is essential to quantify environmental impacts and ensure true sustainability, reinforcing the dual imperative of harnessing innovation and protecting ecosystems. Finally, addressing ethical 4 and regulatory considerations for marine bioprospecting will safeguard marine ecosystems while 5 promoting innovation, ensuring that future exploration adheres to responsible resource utilization 6 principles. 7 8 AUTHOR CONTRIBUTIONS 9 J.Z. took the lead in conceiving the Research Topic and drafted the entire manuscript. J.Z., L.P., and 10 R.Z. participated in the review and revision process to refine the content. All contributing authors 11 have reviewed the final version of the manuscript and approved its publication. 12The authors confirm that no commercial or financial affiliations existed during the research that might 14 be interpreted as giving rise to a potential conflict of interest. 15

Gastric ulcer (GU) represents a clinically significant manifestation of peptic ulcer disease, driven by a complex interplay of microbial, environmental, and immune-inflammatory factors. A recent cross-sectional study by Shen et al systematically evaluated six complete blood count-derived inflammatory indices: Neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation and demonstrated their positive associations with GU prevalence, identifying SIRI as the strongest predictor. This editorial contextualizes these findings within the broader literature, clarifies that these indices reflect systemic rather than GU-specific inflammation, highlights methodological strengths and major limitations, and proposes a conceptual clinical algorithm for integrating SIRI into GU risk assessment. Future multicenter studies incorporating Helicobacter pylori infection, non-steroidal anti-inflammatory drug exposure, and prospective design are essential to validate and translate these findings into clinical practice.