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Discovering new drug candidates for complex diseases like cancer is a significant challenge in modern drug discovery. Drug repurposing provides a cost-effective and time-efficient strategy to identify existing drugs for novel therapeutic targets. Here, we exploited an integrated in-silico approach to identify repurposed drugs that could inhibit programmed death-ligand 1 (PD-L1). PD-L1 is a crucial protein that plays a pivotal role in immune checkpoint regulation, making it a potential target for cancer treatment. Using a drug repurposing approach, we combined molecular docking and molecular dynamics (MD) simulations to study the binding efficiency of FDA-approved drug molecules targeting PD-L1. From the binding affinities and interaction analysis of the first screening, several molecules emerged as PD-L1 binders. Two of them, Lumacaftor and Vedaprofen, showed appropriate drug profiles and biological activities and stood out as highly potent binding partners of the PD-L1. MD simulation was performed for 500 ns to assess the conformational and stability changes of PD-L1-Lumacaftor and PD-L1-Vedaprofen complexes. The simulations revealed sustained structural integrity and stable binding of both complexes throughout the 500 ns trajectories, supporting their potential as PD-L1 inhibitors. While the findings are promising, they remain computational and require experimental validation to confirm biological efficacy and specificity. This study also emphasizes the role of bioinformatics approaches in drug repurposing that can help in the identification of novel anticancer agents.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.

Neurodegenerative diseases (NDs), like Alzheimer’s disease (AD), present immense global health challenges, marked by progressive and irreversible neuronal loss. While many studies have reported the neuroprotective potential of various phytochemicals, the neurotherapeutic relevance of alkaloids, like cinchonine remains largely unexplored. This study for the first time investigates cinchonine, a natural Cinchona alkaloid with reported antioxidant, anti-inflammatory, and amyloid-inhibitory properties, for its interaction with human transferrin (hTf), a glycoprotein central to iron homeostasis and neuroprotection employing a combination of computational and experimental approaches. UV-Vis spectroscopy revealed significant changes in hTf’s absorbance upon cinchonine binding, confirming stable protein-ligand complex formation, with a binding constant ( K ) of 0.7 × 10 5 M − 1 . Fluorescence binding assay further validated the formation of a stable protein-ligand complex. Cinchonine binds with hTf with a binding constant ( K ) of 0.4 × 10 6 M − 1 , signifying the strength of interaction. Molecular docking pinpointed cinchonine’s specific binding site on hTf with a binding affinity of − 6.9 kcal/mol and its interactions with critical residues like Thr392. These findings were reinforced by molecular dynamics (MD) simulations and MM-PBSA, which showcased the stability and conformational integrity of the hTf-cinchonine complex over time. Additionally, hydrogen bonding and free energy analyses provided deeper insights into the molecular basis of the protein-ligand complex. All the findings imply the formation of a stable hTf-cinchonine complex. This study underscores cinchonine’s potential as a therapeutic lead, generating hypotheses for future experimental validation of its efficacy in preventing or mitigating NDs.

[This corrects the article DOI: 10.3389/fncel.2025.1681891.].

Plants encounter various stresses in their natural environments and can effectively respond to only one stress at a time. Through a complex gene network, transcription factors (TFs) such as WRKY TFs regulate a diverse array of stress responses. The clarification of the structural characteristics of WRKY proteins, along with recent advancements in molecular dynamics simulations, has shed light on the formation, stability, and interactions of DNA–protein complexes. This has provided a novel viewpoint regarding the control of WRKY TFs. The investigation of superfamilies, encompassing their historical development, diversity, and evolutionary patterns, has become feasible due to the transcriptome approach’s capacity to provide extensive and comprehensive transcripts. The significance of WRKY TFs lies in their pivotal role within several signaling cascades and regulatory networks that influence plant defense responses. The present review summarizes the functional aspects of the high-volume sequence data of WRKY TFs from different species studied to date. Moreover, a comparative analysis approach was utilized to determine the functions of the identified WRKY TFs in response to both abiotic and biotic stresses, as revealed through numerous studies on different plant species. The results of this review will be pivotal in understanding evolutionary events and the significance of WRKY TFs in the context of climate change, incorporating new scientific evidence to propose an innovative viewpoint.

This study provides insight into therapy for lung cancer, establishing p-C resol ( p-C) as an inhibitor of Pyruvate Dehydrogenase Kinase 3 (PDK3). PDK3 is critical in cancer metabolism by regulating the pyruvate dehydrogenase complex, shifting cellular energy production towards glycolysis, and promoting tumor growth and survival under hypoxic conditions. In this study, we have used computational and experimental approaches. Molecular docking reveals that p-C occupies PDK3’s binding pocket and forms interactions with key residues, especially Asp 287. Molecular dynamic simulation (MD) studies showed that p-C induced minimum alterations in PDK3, suggesting the structural stability of the PDK3- p-C complex. A fluorescence-based binding study demonstrated the binding of p-C to PDK3 with a binding constant of 3.8 × 10 8 M −1 , indicating excellent binding affinity. Cell-based enzyme assay revealed significant inhibition of PDK3 by p-C , establishing it as a PDK3 inhibitor. Moreover, cellular assays also demonstrated significant inhibition of PDK3 activity and tumor progression. This study provides a promising therapeutic avenue for improving lung cancer treatment outcomes by targeting PDK3. 

Histone deacetylase 11 (HDAC11) is a member of the HDAC family that plays a crucial role in epigenetic regulation, influencing key cellular processes like transcription, differentiation, and proliferation. Abnormal expressions and functions of HDAC11 have been described in various diseases, including neurodegenerative diseases and cancer, highlighting its potential as a promising therapeutic target. Despite its biological significance, selective HDAC11 inhibitors remain largely unexplored, presenting a critical research gap in the development of targeted epigenetic therapies. Drug repurposing provides a cost‐effective and time‐efficient strategy for accelerating the discovery of novel therapeutics by leveraging the established safety profiles of approved drugs. Here, we report a computational drug repurposing approach to screen FDA‐approved drugs for their ability to inhibit HDAC11. Subsequently, we virtually screened 3500 drugs and shortlisted pimozide and nilotinib as promising candidates, based on high docking scores and protein interaction patterns. Further molecular dynamics (MD) simulations for 500‐ns trajectories demonstrated that pimozide and nilotinib maintain stable protein–ligand contacts with residues lining the HDAC11 catalytic pocket in an AlphaFold‐derived apo model. Because the AlphaFold coordinate file used here does not contain the catalytic Zn 2+ ion, these simulations do not evaluate possible ligand–Zn 2+ coordination or metal‐dependent inhibition. MM‐PBSA‐based binding free energy calculations were conducted to estimate binding propensities in the apo context; however, metal‐aware structural modeling and biochemical assays are required to determine whether observed binding translates to Zn 2+ ‐dependent enzyme inhibition and isoform selectivity.

The Indian pangolin (Manis crassicaudata; Manidae, Pholidota), a species categorized as “Endangered” on the IUCN Red List, is one of nine extant pangolin species in Asia. This study investigated habitat preference, habitat suitability, and illegal trade routes of the Indian pangolin in Pakistan's Khyber Pakhtunkhwa province. Habitat preference was determined by analyzing the distribution and density of pangolin signs across various land cover types. Habitat suitability for the species was assessed using the MaxEnt modeling approach and field data. Trade routes were identified using information from hunters, poachers, dealers, and local communities to understand the threats related to illegal wildlife trafficking. Results indicated significant differences in burrow distributions across habitats (χ2 = 17.756, df = 6, p < 0.01), which suggest ecological preferences and adaptations. We complemented MaxEnt with Random Forest and Support Vector Machine models trained with the same predictors and spatial folds to validate robustness and characterize non‐linear effects. Across held‐out folds, SVM performed best, with RF and MaxEnt yielding comparable but lower discrimination; a TSS‐weighted ensemble provided a stable consensus SVM (mean AUC ≈ 0.61; TSS ≈ 0.33). Variable‐importance and partial‐dependence analyses consistently highlighted Elevation, NDMI, and NDWI as influential predictors. Several routes used for the illegal trade of Indian pangolin scales and whole animals were identified. The study also highlights the ongoing issues of illegal poaching and habitat intrusion, worsened by low local awareness and inadequate enforcement. The findings support a comprehensive conservation strategy that includes strict enforcement of wildlife protection laws, increased penalties for poaching, community‐based monitoring through targeted awareness campaigns, local wildlife patrols, and ongoing scientific research to support habitat restoration, adaptive management, and evidence‐based policy development. Community‐based conservation initiatives and improved wildlife law enforcement at key trafficking hubs could significantly reduce poaching pressure. This study assessed habitat preferences, suitability, and illegal trade routes of the endangered Indian pangolin in Pakistan's Khyber Pakhtunkhwa province. Using field surveys and MaxEnt modeling, we identified fragmented habitats with only 22% classified as highly suitable, alongside key poaching and trafficking pathways. Findings emphasize the need for integrated conservation efforts combining habitat protection, community engagement, and stronger law enforcement.

Background: Hepatitis B virus (HBV)–associated liver cirrhosis, characterized by progressive fibrosis and regenerative nodule formation, remains a critical public health concern due to its high risk of progression to hepatocellular carcinoma (HCC). The matrisome—comprising extracellular matrix (ECM) components such as collagens, laminins, fibronectin, glycoproteins, and proteoglycans—plays a pivotal role in disease pathogenesis. Previous studies have shown that HBV infection modulates ECM composition and activates fibrogenic responses through hepatic stellate cells, contributing to cirrhosis and eventual HCC development. However, key ECM‐related genes driving HBV‐induced cirrhosis remain poorly understood. Methods: Bulk RNA‐seq data from 30 normal and 30 HBV‐related cirrhotic liver tissues were analyzed. Differentially expressed genes (DEGs) were identified using the Limma package based on thresholds of p < 0.01 and |log2 fold change| > 1. ECM‐related genes were curated from the Molecular Signatures Database (MsigDB). Functional significance was assessed via random forest classification ( accuracy : 91%, recall : 90%), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Results: Among 14,470 analyzed genes, 2125 were upregulated and 3689 downregulated in cirrhotic tissues. Upregulated genes ( COX6B1 , RPS10 ) were linked to metabolic reprogramming, while downregulated genes ( PLCG2 , ARHGEF12 ) implicated immune dysregulation. A subset of 274 ECM‐related DEGs (178 upregulated, 96 downregulated) was identified, including CTSA , CRELD2 , MAPK10 , and ITGA1 . Pathway analysis highlighted dysregulation of Ras/MAPK and ERBB signaling pathways associated with fibrogenesis and tumorigenesis. Conclusions: This bioinformatics study delineates key matrisome–associated genes and pathways in HBV‐related cirrhosis, offering novel insights into potential biomarkers and therapeutic targets. Further validation in larger cohorts is warranted to confirm clinical relevance.

Oral squamous cell carcinoma (OSCC) remains difficult to treat because of its intricate molecular profile, its limited responsiveness to conventional therapeutic approaches, and the challenge of targeting key oncogenic drivers with standard drugs. An emerging approach that addresses these limitations is the use of proteolysis-targeting chimeras (PROTACs), which shifts the focus from traditional inhibition of protein activity to the deliberate degradation of disease-associated proteins. PROTACs can eliminate oncogenic proteins like EGFR, STAT3, c-MYC, and anti-apoptotic regulators by hijacking the ubiquitin-proteasome system, many of which are essential for OSCC pathophysiology and are considered undruggable. This method provides a catalytic, sustained mechanism of action and overcomes the resistance arising from target overexpression, mutation, or signaling redundancy. Recent advances in PROTAC design, consisting of orally bioavailable degraders and tissue-directed delivery systems, highlight their translational capacity in epithelial tumors. PROTACs enable degradation of critical effectors involved in proliferation, immune evasion, and therapy resistance in OSCC. Hence, this review highlights how PROTAC technology addresses the current molecular targeting gaps in OSCC and outlines future directions for translating targeted protein degradation into clinical therapy.