Mechanotransduction, converting physical forces into biochemical signals, has emerged as a key regulatory mechanism in cancer. The Piezo family (Piezo1 and Piezo2) is critical mechanically activated ion channels that transduce mechanical stimuli into intracellular calcium flux, influencing proliferation, migration, and differentiation. Emerging evidence strongly implicates their dysregulation in shaping cancer phenotypes and remodeling of the tumor microenvironment. Altered Piezo expression occurs in multiple malignancies (e.g., breast, lung, and colorectal cancer), correlating with progression, metastasis, and clinical outcomes. Piezo channels also intersect with immune and angiogenic pathways, extending the mechanical influence to the tumor ecosystem. Thus, Piezos act as central integrators of tumor physiology by integrating mechanical stress with biochemical and immune signaling. However, translating Piezo-targeted interventions into clinical practice remains challenging. This perspective summarizes current understanding of Piezos' structure and gating, their roles in cancer, and the opportunities and obstacles for Piezo-based therapy, aiming to delineate future translational pathways.

Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an essential regulator in the initiation of autophagy and represents a novel therapeutic target for colorectal cancer (CRC) treatment. Herein, we developed a series of novel ULK1 covalent inhibitors through structure-based and medicinal chemistry optimizations. Notably, compound 12i was synthesized and validated to form covalent bonds with ULK1, exhibiting pronounced selectivity and potent inhibitory activity (ULK1 IC50 = 4.7 μM). Moreover, 12i demonstrated anti-proliferative effects in CRC cell lines. In vitro experiments showed that 12i effectively inhibited CRC cell growth, induced cell cycle arrest at the S or G2/M phase, and triggered apoptosis by blocking ULK1-mediated autophagy. Additionally, in vivo results showed that 12i also exhibited good tumor inhibitory activity in CRC murine models, with an inhibition rate of 70.4 % at 40 mg/kg. In vivo pharmacokinetic studies revealed moderate systemic absorption (Tmax = 2 h) with oral bioavailability of 39.7 % in rats. In summary, our findings highlight compound 12i as a promising lead candidate for further development of selective ULK1 covalent inhibitors, offering a potential new strategy for CRC therapy.

G9a is a SET domain-containing histone methyltransferase that catalyzes H3K9 methylation to regulate gene transcription. Recent studies have revealed that G9a exerts both catalytic and non-catalytic functions in tumor progression and inflammatory diseases, establishing it as a promising therapeutic target. Herein, we developed L4 by using proteolysis targeting chimera (PROTAC) technology. L4 induces G9a degradation through the ubiquitin-proteasome system (UPS) in both a concentration- and time-dependent manner (DC50 = 1.29 μM), while substantially reducing H3K9me2 expression levels. Through molecular dynamics (MD) simulations, we elucidated the binding mode and key interactions of L4, as well as the stable conformation of the G9aSET-L4-CRBNTBD ternary complex. Quantitative proteomics results demonstrated that L4 selectively targets G9a. In tumor models, L4 not only inhibits triple-negative breast cancer (TNBC) cell proliferation in vitro but also promotes apoptosis and suppresses cell migration. Furthermore, we investigated the therapeutic potential of L4 in inflammatory disorders, particularly psoriasis. L4 inhibited HaCaT cell proliferation, promoted G9a degradation, and suppressed NF-κB signaling. In vivo results showed that L4 dose-dependently alleviated skin inflammation, reduced epidermal hyperplasia, and decreased Ki67 expression, showing superior efficacy to BIX01294. Mechanistically, these effects were associated with the downregulation of G9a and NF-κB, while L4 also exhibited favorable local safety. Taken together, the development of L4 presents an innovative approach for designing G9a-targeting PROTAC molecules and offers new therapeutic possibilities for cancer and inflammatory diseases driven by non-enzymatic functions of G9a.

Class III phosphatidylinositol 3-kinase (PtdIns3K) occupies the nexus of autophagy and endomembrane trafficking. Within its core complex, the VPS34 catalytic subunit partners with VPS15, Beclin-1, and ATG14L or UVRAG to convert phosphatidylinositol into PtdIns3P-the lipid cue that seeds phagophore nucleation and endosome-lysosome maturation. By tuning this single signaling node, cells safeguard proteostasis and orchestrate rapid stress responses; when this regulatory network is disrupted, PtdIns3K dysregulation fuels neurodegeneration, tumor progression, immune imbalance, and metabolic disease. This review fuses cutting-edge structural and biochemical insights into PtdIns3K, dissects its multilayered regulation-spanning post-translational modifications, adaptor engagement, and higher-order assembly-and appraises next-generation small-molecule inhibitors designed for precision autophagy control. Decoding and therapeutically exploiting this pathway will open a new chapter in the discovery of innovative therapeutic approaches.

ABSTRACT Equivariant graph neural networks (EGNNs) are becoming the geometric infrastructure of 3D molecular generation for AI‐aided drug discovery. By enforcing E(n), E(3), or SE(3) equivariance, they separate physical molecular structure from arbitrary coordinate‐frame conventions and ensure that predicted coordinates, denoising directions, and velocity fields transform consistently with molecular geometry. This symmetry‐aware design supports direct modeling of conformations and protein–ligand spatial relationships while remaining compatible with diffusion, flow‐based, autoregressive, and hybrid generative frameworks. Consequently, EGNNs enable more geometrically consistent generation and facilitate controllable design conditioned on binding pockets, pharmacophores, fragments, scaffolds, reference ligands, or molecular properties. Their benefits, however, are bounded by what equivariance encodes. Coordinate‐frame consistency does not itself enforce valid bonds, valence, stereochemistry, topology–geometry agreement, synthesizability, or biological activity. Moreover, practical models must reconcile discrete chemical variables with continuous geometric dynamics, represent long‐range interactions without prohibitive computational cost, and account for protein flexibility, solvent, metal ions, and induced fit. Performance is further constrained by biased docking or property predictors, heterogeneous benchmarks, and limited prospective validation. This review synthesizes how EGNNs function across major generative paradigms and argues that future drug‐oriented systems should combine joint 2D–3D graph generation, physically credible interaction modeling, synthesis and ADMET constraints, multi‐objective optimization, and closed‐loop experimental feedback. EGNNs should therefore be viewed not as a complete chemical solution, but as the symmetry‐aware foundation upon which more testable and biologically relevant molecular design systems can be built.

Objective This study aimed to investigate the therapeutic effects of parthenolide, a sesquiterpene lactone derived from Tanacetum parthenium (feverfew), on hepatocellular carcinoma (HCC), with particular focus on its mechanism of action involving the induction of endoplasmic reticulum (ER) stress mediated cell death pathways. Methods This study employed an integrated methodological framework combining molecular pharmacological phenotype analysis, mRNA sequencing, and bioinformatics analysis. Initially, the phenotypic effects of parthenolide on human hepatocellular carcinoma 3B cell line (Hep3B) and Shanghai Medical College hepatoma 7721 cell line (SMMC-7721) were systematically assessed using colony formation assays and wound-healing assays to evaluate anti-proliferative and anti-metastatic activities, respectively. Programmed cell death was quantitatively analyzed via flow cytometry and key molecular markers were examined by Western blotting. The mRNA sequencing was employed to conduct a comprehensive analysis of gene expression profile changes in HCC cells induced by parthenolide treatment. Targets and pathways identified, especially those related to response to ER stress and unfolded protein response (UPR), were then prioritized for molecular validation. Results Parthenolide treatment exerted significant anti-proliferative, anti-metastatic, and cell death-inducing effects on HCC cells. These effects were attributed to excessive ER stress response triggered by parthenolide, which significantly altered the activation state of eukaryotic initiation factor 2α (eIF2α), a key regulator of protein translation and synthesis. Bioinformatics analysis revealed strong associations between parthenolide treatment and ER stress, topologically incorrect protein response, and unfolded protein response processes. Furthermore, parthenolide treatment increased eIF2α phosphorylation levels and upregulated expression of activating transcription factor 4 (ATF4) and glucose-regulated protein 78 kDa (GRP78). The hyperactivated ER stress response subsequently activated apoptotic and autophagic signaling pathways within HCC cells, leading to programmed cell death. Conclusion Parthenolide effectively inhibits hepatocellular carcinoma cell proliferation and promotes cell death by enhancing eIF2α phosphorylation and inducing ER stress mediated apoptosis and autophagy. These findings provide compelling experimental evidence supporting parthenolide as a promising therapeutic candidate for HCC treatment targeting ER stress pathways.

High Mobility Group Box 1 (HMGB1) is a nuclear protein crucial for nucleosome stability, gene regulation, DNA repair, cell differentiation, and development. Extracellularly, HMGB1 functions as a cytokine, significantly impacting inflammation, immune response, and the pathogenesis of various diseases, including cancer and inflammatory disorders. Research highlights HMGB1's complex role in cancer, where it promotes tumorigenesis through chronic inflammation and immune suppression while enhancing chemotherapy and genome stability. It also influences cell proliferation, angiogenesis, metastasis, and chemotherapy resistance. In inflammatory diseases, HMGB1 has a dual role: it can promote inflammation in conditions like ischemia-reperfusion injury and sepsis but also induces immune tolerance and suppression. This review provides a comprehensive overview of HMGB1's structure, functions, and regulatory mechanisms, discussing recent advances in understanding its roles in cancer and inflammatory diseases. We emphasize the evolving therapeutic strategies targeting HMGB1, underscoring its potential as a promising target for treating both cancer and inflammatory disorders.

Background: EMP2 is a tumor-associated membrane protein belonging to the GAS-3/PMP22 gene family. EMP2 expression demonstrates significant tissue specificity and heterogeneity in various human tissues and tumor tissues, where it may play a role in either promoting or inhibiting tumor growth. This study aimed to investigate the expression level, biological functions, and molecular mechanisms of EMP2 in liver cancer. Methods: we analyzed the mRNA expression levels of EMPs family genes in hepatocellular carcinoma (HCC) tissues and normal liver tissues based on the TCGA database and immunohistochemical analysis of tissue microarrays. Subsequently, we constructed HCC cell lines with either knockdown or overexpression of EMP2 to examine the biological functions and molecular mechanisms of EMP2 in tumorigenesis in vivo and in vitro. Results: Bioinformatic and immunohistochemical analysis of tissue microarrays have confirmed the significant upregulation of EMP2 in HCC tissues. In vitro and in vivo studies have shown that downregulation of EMP2 results in a moderate reduction in the proliferation and invasive capacity of HCC cells. Conversely, overexpression of EMP2 enhances the invasive capacity of HCC cells and induces autophagy. Initial investigations into the molecular mechanisms underlying EMP2-mediated enhancement of HCC cell invasion have revealed the dual regulation of EMP2-induced autophagy and the integrin pathway, which synergistically influence the invasive and metastatic potential of HCC cells. Conclusion: EMP2 holds promise as a diagnostic marker for HCC metastasis and a potential target for targeted therapy.

Colorectal cancer (CRC) ranks among the leading causes of cancer-related dea ths worldwide, and the rising incidence and mortality of CRC underscores the urgent need for better understanding and management strategies. Icaritin (ICA) is the metabolites of icariin, a natural flavonoid glycoside compound derived from the stems and leaves of Epimedium. It has broad spectrum antitumor activity and inhibits the proliferation, migration, and invasion of CRC cells, and causes S phase cell cycle arrest. It exerts its antitumor effects against CRC through repressing autophagy to promote CRC cell apoptosis via interfering the HSP90-TXNDC9 interactions. The safety and efficacy of ICA are also affirmed in a mouse xenograft model. Additionally, to test whether ICA exerts synergistic effects with low-temperature photothermal therapy (LTPTT), a novel nanodrug delivery system, employing SiO2 nanocarriers, is designed aiming to load ICA with photothermal materials polydopamine (PDA), and folic acid (FA). This SiO2/Ica-PDA-FA multifunctional nanocomposite actively targets tumor tissues through the high affinity of FA for cancer cells. Once internalized, the acidic intracellular environment triggers the controlled release of ICA, inhibiting HSP90-TXNDC9 interactions. By LTPTT and ICA drug therapy under near-infrared illumination, a dual synergistic antitumor effect is achieved, holding promise for enhancing therapeutic outcomes in CRC treatment.

As the most abundant and essential structural protein in the human body, collagen is ubiquitously present in the interstitium of nearly all solid organs, playing a crucial role in maintaining the structural integrity and functional stability of human tissues and organs. Disorders associated with collagen structure and metabolisms impose a significant burden on society and healthcare systems. Post-translational modifications (PTMs) are essential steps in collagen metabolism, and recent studies have indicated that aberrant regulation of PTMs plays a pivotal role in the pathogenesis and progress of collagen-related disorders, including liver, kidney, heart, lung, and skin fibrosis, as well as keloid. This review provides a comprehensive summary of the regulatory mechanisms of both traditional and novel PTMs in collagen metabolism and collagen-related diseases. Furthermore, we summarize the drugs that modulate PTMs and their effects, with the aim of elucidating the pathophysiology of collagen-related diseases and provide new insights for their diagnosis, prevention, and treatment.

Programmed cell death (PCD) is characterized as a cell death pathway governed by specific gene-encoding requirements, plays crucial roles in the homeostasis and innate immunity of organisms, and serves as both a pathogenic mechanism and a therapeutic target for a variety of human diseases. Z-DNA-binding protein 1 (ZBP1) functions as a cytosolic nucleic acid sensor, utilizing its unique Zα domains to detect endogenous or exogenous nucleic acids and its receptor-interacting protein homotypic interaction motif (RHIM) domains to sense or bind specific signaling molecules, thereby exerting regulatory effects on various forms of PCD. ZBP1 is involved in apoptosis, necroptosis, pyroptosis, and PANoptosis and interacts with molecules, such as receptor-interacting protein kinase 3 (RIPK3), to influence cell fate under various pathological conditions. It plays a crucial role in regulating PCD during infections, inflammatory and neurological diseases, cancers, and other conditions, affecting disease onset and progression. Targeting ZBP1-associated PCD may represent a viable therapeutic strategy for related pathological conditions. This review comprehensively summarizes the regulatory functions of ZBP1 in PCD and its interactions with several closely associated signaling molecules and delineates the diseases linked to ZBP1-mediated PCD, along with the potential therapeutic implications of ZBP1 in these contexts. Ongoing research on ZBP1 is being refined across various disease models, and these advancements may provide novel insights for studies focusing on PCD, potentially leading to new therapeutic options for related diseases.

Galectins play pivotal roles in cellular recognition and signaling processes by interacting with glycoconjugates. Extensive research has highlighted the significance of Galectins in the context of cancer, aiding in the identification of biomarkers for early detection, personalized therapy, and predicting treatment responses. This review offers a comprehensive overview of the structural characteristics, ligand-binding properties, and interacting proteins of Galectins. We delve into their biological functions and examine their roles across various cancer types. Galectins, characterized by a conserved carbohydrate recognition domain (CRD), are divided into prototype, tandem-repeat, and chimera types based on their structural configurations. Prototype Galectins contain a single CRD, tandem-repeat Galectins contain two distinct CRDs linked by a peptide, and the chimera-type Galectin-3 features a unique structural arrangement. The capacity of Galectins to engage in multivalent interactions allows them to regulate a variety of signaling pathways, thereby affecting cell fate and function. In cancer, Galectins contribute to tumor cell transformation, angiogenesis, immune evasion, and metastasis, making them critical targets for therapeutic intervention. This review discusses the multifaceted roles of Galectins in cancer progression and explores current advancements in the development of Galectin-targeted therapies. We also address the challenges and future directions for integrating Galectin research into clinical practice to enhance cancer treatment outcomes. In brief, understanding the complex functions of Galectins in cancer biology opens new avenues for therapeutic strategies. Continued research on Galectin interactions and their pathological roles is essential for developing effective carbohydrate-based treatments and improving clinical interventions for cancer patients.

Molecular mechanisms of chaperone-mediated autophagy (CMA) constitute essential regulatory elements in cellular homeostasis, encompassing protein quality control, metabolic regulation, cellular signaling cascades, and immunological functions. Perturbations in CMA functionality have been causally associated with various pathological conditions, including neurodegenerative pathologies and neoplastic diseases. Recent advances in targeted protein degradation (TPD) methodologies have demonstrated that engineered degraders incorporating KFERQ-like motifs can facilitate lysosomal translocation and subsequent proteolysis of noncanonical substrates, offering novel therapeutic interventions for both oncological and neurodegenerative disorders. This comprehensive review elucidates the molecular mechanisms, physiological significance, and pathological implications of CMA pathways. Additionally, it provides a critical analysis of contemporary developments in CMA-based degrader technologies, with particular emphasis on their structural determinants, mechanistic principles, and therapeutic applications. The discourse extends to current technical limitations in CMA investigation and identifies key obstacles that must be addressed to advance the development of CMA-targeting therapeutic agents.

Organ injury represents one of the leading causes of mortality worldwide, severely impacting patients' quality of life while imposing substantial economic and psychological burdens. Both hepatic and pulmonary injuries can trigger pro-inflammatory cascades, subsequently promoting fibrosis, cirrhosis, and ultimately organ failure. Organ fibrosis is characterized by excessive extracellular matrix deposition and is strongly associated with increased morbidity and mortality. In this study, we designed and synthesized a series of novel compounds based on JQ-1 and anethole trithione (ATT) that simultaneously release hydrogen sulfide (H2S) and inhibit bromodomain and extraterminal domain proteins (BET), with the aim of attenuating liver and lung injuries. Among these compounds, 11r demonstrated exceptional efficacy in H2S release and significantly suppressed the CCl4-induced upregulation of fibrosis markers (α-SMA and fibronectin), c-Myc, and CDC25B, while also reducing cellular apoptosis in LO2 hepatocytes. In a CCl4-induced murine liver fibrosis model, daily oral administration of 11r (30 mg/kg) for three consecutive days significantly improved hepatic function, restored damaged liver architecture, and reduced collagen deposition, exhibiting superior therapeutic efficacy compared to JQ-1 or ATT monotherapy. Furthermore, 11r extended the survival duration of CCl4-treated mice and mitigated systemic damage including spleen and lungs. Notably, 11r also enhanced pulmonary function and diminished collagen accumulation in a bleomycin (BLM)-induced murine pulmonary fibrosis model. Our studies demonstrate that compound 11r represents a promising therapeutic candidate for the treatment of hepatic and pulmonary fibrosis. This study not only highlights the potential synergistic benefits of combining BRD4 inhibition with H2S donation for fibrotic disease management but also establishes a foundation for future clinical investigations and mechanistic studies to further elucidate the underlying pharmacological mechanisms.

Background Regulated cell death (RCD) is essential for organismal development, as it plays key roles in organ formation, pathogen defense, and the maintenance of homeostasis. However, while RCD subroutines-such as apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis-are fundamental for health, their dysregulation can be detrimental, potentially triggering or contributing to a variety of diseases. As a result, the modulation of RCD has emerged as a promising therapeutic strategy for numerous conditions, including infectious, neurodegenerative, autoimmune, cardiovascular diseases, and cancer. Over the past two decades, innovative experimental approaches for modulating RCD have proliferated in medicinal research. In parallel, a growing array of online resources-such as databases, web servers, machine learning (ML) /artificial intelligence (AI) models, omics technologies, and systems biology networks, collectively referred to as “in silico methods”-has become available to accelerate research progress. Aim of review Recognizing the potential of these online resources, we have compiled a comprehensive overview of relevant in silico approaches to RCD, aiming to facilitate their effective use in the development of future therapeutic interventions. Key scientific concepts of review RCD-associated databases serve as the foundational data infrastructure for in silico methods, encompassing extensive biological information spanning DNA, RNA, proteins, small molecules, and disease-related data. The continuous curation and expansion of these databases are crucial for elucidating various cell death modalities and visually characterizing the functional dynamics of target molecules across different pathological conditions. Through the integration of AI, ML, multi-omics technologies, and systems biology approaches, we can systematically decode the intricate regulatory networks of RCD and disease progression patterns. This interdisciplinary convergence significantly enhances the discovery pipeline for disease-specific biomarkers and therapeutic targets.

Epithelial membrane protein 2 (EMP2) plays crucial roles in cell proliferation, migration, and adhesion. Despite its importance, conventional EMP2 RNAi therapy shows limited efficacy in vivo. We therefore developed a novel RNA-delivery system utilizing self-assembling defense peptide-cholesterol conjugates for efficient EMP2-siRNA transfection. The engineered HH2-siEMP2 nanoparticles exhibited optimal size and positive surface charge, conferring excellent serum stability and enhanced cellular uptake in breast cancer cell lines. These nanoparticles effectively silenced EMP2 expression, leading to significant suppression of tumor migration and invasion in both in vitro and in vivo models. Beyond direct anti-tumor effects, the HH2-C conjugate demonstrated immunomodulatory properties by promoting Th1 cell expansion, reducing Th2 cells and immunosuppressive Tregs, and restoring Th17/Treg balance. These findings establish EMP2 as a promising therapeutic target in breast cancer and highlight the potential of HH2-C-based nanoparticles as a dual-function platform combining efficient siRNA delivery with immunostimulatory activity.

Acne vulgaris is a common chronic inflammatory skin disorder with significant clinical and societal impacts. Severe acne (SA), in particular, causes scarring, disfigurement, and psychosocial distress. The underlying pathogenesis of SA remains poorly understood, hindering the development of effective treatments. In our study, single-cell RNA sequencing (scRNA-seq) of samples from SA, acne, and normal skin was performed, 12 clusters were identified from the total cell population, and macrophages were considered as important cell clusters since all gene modules showed high gene activity for macrophages in the scRNA weighted correlation network analysis (WGCNA). By integrating macrophage-specific differentially expressed genes (DEGs) with Mendelian randomization (MR) analysis, it was found that T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) was identified as a potential immune checkpoint involved in the development of SA. Multiplex immunohistochemistry (mIHC) revealed a decreased tendency for TIM3+ neutrophils, an increased presence of TIM3+ macrophages (especially TIM3+ M2 macrophages), and a reduced population of TIM3+ keratinocytes in SA tissues compared to controls. In human immortalized keratinocytes (HaCaT) cells, TIM3 knockdown led to the upregulation of Propionibacterium acnes (P. acnes)-induced proinflammatory cytokine secretion, and the administration of an anti-Tim3 antibody in P.acnes induced mouse model exacerbated acne-associated inflammation. Collectively, these findings support a role for TIM3 in SA and suggest TIM3 as a potential therapeutic target, while underscoring the immunomodulatory function of keratinocytes and providing directions for future investigations.

Zanthoxylum bungeanum Maxim., commonly known as Chinese prickly ash, is a well-known spice and traditional Chinese medicine ingredient with a rich history of use in treating inflammatory conditions. This review provides a comprehensive overview of the botanical classification, traditional applications, and anti-inflammatory effects of Z. bungeanum, with a specific focus on its polyphenolic components. These polyphenols have exhibited considerable promise, as evidenced by preclinical studies in animal models, suggesting their therapeutic potential in human inflammatory diseases such as ulcerative colitis, arthritis, asthma, chronic obstructive pulmonary disease, cardiovascular disease, and neurodegenerative conditions. This positions them as a promising class of natural compounds with the potential to enhance human well-being. However, further research is necessary to fully elucidate their mechanisms of action and develop safe and effective therapeutic applications.

Protease-activated receptor 2 (PAR2) is a cell-surface receptor expressed in various cell types, including keratinocytes, neurons, immune and inflammatory cells. Activation of PAR2, whether via its canonical or biased pathways, triggers a series of signaling cascades that mediate numerous functions. This review aims to highlight the emerging roles and interactions of PAR2 in different skin cells. It specifically summarizes the latest insights into the roles of PAR2 in skin conditions such as atopic dermatitis (AD), psoriasis, vitiligo and melasma. It also considers these roles from the perspective of the cutaneous microenvironment in relation to other inflammatory and autoimmune dermatological disorders. Additionally, the review explores PAR2’s involvement in associated comorbidities from both cutaneous and extracutaneous diseases. Therefore, PAR2 may serve as a key target for interactions among various cells within the local skin environment.