The Potential Role and Mechanism of RBM47-Mediated Genes in Atherosclerosis

The Molecular Structure, Expression, and Emerging Role of the 15-Leucine-Rich Repeat Containing Membrane Protein (LRRC15) in Skeletal Biology and Diseases

The 15-leucine-rich repeat containing membrane protein (LRRC15) is a transmembrane protein derived from the leucine-rich repeat (LRR) superfamily that participates in various cell–cell and cell–extracellular matrix interactions, regulating fibrogenesis, vascular invasion, tumorigenesis, and the formation of the innate immune barrier to drive specific antiviral responses. LRRC15, whose expression is reportedly induced by TGF-β and IL-1β stimulation, was recently found to be associated with the development of skeletal diseases, and its presence has been related to the pathophysiological processes of osteoporosis, osteoarthritis and rheumatoid arthritis. Various transmembrane and intracellular signaling transductions are involved in LRRC15-mediated molecular functions, including integrin, NF-κB, Wnt/β-catenin, etc. Additionally, LRRC15 is considered a novel mesenchymal protein and an important biomarker for the occurrence and development of osteosarcoma. Understanding the role of LRRC15 in the bone, joint and tumor microenvironment will facilitate the development of new therapeutic options—particularly LRRC15-based target therapies—for skeletal diseases.

ABTB1, as an E3 ubiquitin ligase, suppresses Th17 cell differentiation and mitigates autoimmune inflammation by promoting STAT3 ubiquitination and degradation.

The emerging role of ZDHHC9 in cancer: from protein palmitoylation to tumor progression and immune regulation

Protein S-palmitoylation, and more broadly protein S-acylation when acyl donors other than palmitoyl-CoA are involved, is an emerging post-translational mechanism in cancer that dynamically regulates protein stability, membrane localization, trafficking, and signaling output. Among the zinc finger DHHC-type palmitoyl acyltransferases, ZDHHC9 has attracted increasing attention because of its expanding roles across multiple malignancies. Accumulating evidence indicates that ZDHHC9 is frequently dysregulated in cancer and contributes to tumor progression through palmitoylation-dependent regulation of proteins involved in oncogenic signaling, stress adaptation, metabolic rewiring, and immune evasion. Functionally, ZDHHC9 has been linked to the modulation of substrates such as BiP/GRP78, CD38, STAT1, PD-L1, and PCBP1, thereby influencing unfolded protein response signaling, checkpoint-related immune suppression, ferroptosis-associated pathways, and tumor cell survival. Beyond its tumor-intrinsic effects, ZDHHC9 is increasingly recognized as a regulator of the tumor immune microenvironment, with emerging evidence showing that it can suppress effector CD8+ T-cell responses and reduce sensitivity to immune checkpoint blockade in selected cancer contexts. In this review, we summarize the molecular basis of ZDHHC9, discuss its roles in tumor progression and immune regulation, and highlight current advances and challenges in therapeutic targeting. A deeper understanding of ZDHHC9-dependent palmitoylation networks may support the development of new biomarkers and precision anticancer strategies.

Role of PCSK9 in hallmarks of cancer: From mechanisms to interventions (Review)

Although the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in regulating cholesterol homeostasis through low-density lipoprotein receptor (LDLR) is well established, accumulating evidence underscores its broader involvement in diverse biological processes such as angiogenesis and immunoregulation. These functions implicate PCSK9 in the pathogenesis of various human diseases, including cancer. Recent studies have revealed that PCSK9 mediates the lysosomal degradation of multiple substrates beyond LDLR, thereby expanding its potential importance in oncology. To the best of our knowledge, the present review summarized for the first time the identified repertoire of PCSK9 substrates, emphasising how these interactions enable PCSK9 to regulate novel biological pathways independently of cholesterol metabolism. Next, PCSK9 genetic variants were compiled, documented and discussed, focusing on how they influence disease susceptibility and progression by modulating PCSK9 activity or expression. Finally, the present review elaborated on the mechanisms by which PCSK9 contributes to several hallmarks of cancer, including sustained proliferative signaling, invasion and metastasis, metabolic reprogramming, angiogenesis and tumor immune evasion through the modulation of specific substrates. These insights highlight its relevance as a therapeutic target. The current review also provides an overview of ongoing clinical trials evaluating PCSK9 inhibitors, either as monotherapy or in combination with other anticancer strategies. Altogether, these advances lay a foundation for personalized and precision cancer therapy.

Structure-Based Identification of HFS764 as an Inhibitor of the HIF-1α–p300 Interface in Hypoxic Renal Cell Carcinoma

Background: Hypoxia-inducible factor-1 alpha (HIF-1α) drives tumor adaptation to hypoxia by promoting angiogenesis, metabolic reprogramming, and survival signaling in clear cell renal cell carcinoma (ccRCC). Transcriptional activity of HIF-1α depends on its interaction with the p300/CBP (CREB-binding protein) coactivator via the C-terminal transactivation domain (C-TAD). Direct targeting of this protein–protein interface remains limited, highlighting the need for novel inhibitors.Methods: A structure-based virtual screening of ~250,000 compounds from the ZINC database was conducted to identify candidates targeting a predicted pocket within the HIF-1α C-TAD. Top hits were evaluated using molecular docking and 100 ns molecular dynamics simulations. The lead compound, HFS764, was further characterized using in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling, homogeneous time-resolved fluorescence (HTRF) assays, and differential scanning fluorimetry (DSF). Functional effects were assessed in Caki-1 cells under hypoxia using hypoxia response element (HRE)-luciferase assays, cell viability and vascular endothelial growth factor (VEGF) secretion.Results: HFS764 demonstrated stable binding within the HIF-1α pocket, with ligand root-mean-square deviation (RMSD) <0.20 nm and a predicted binding free energy of –22.38 kcal/mol. HTRF assays confirmed inhibition of the HIF-1α–p300 interaction (IC50 = 4.89 μM), while DSF showed ligand-induced stabilization (ΔTm = +2.0 °C). In Caki-1 cells, HFS764 suppressed HRE-driven transcription (IC50 = 4.27 μM), and reduced VEGF secretion under hypoxia. Selective cytotoxicity was observed (GI50: 14.70 μM in Caki-1 vs. 37.98 μM in HK-2; therapeutic index = 2.58).Conclusion: HFS764 disrupts the HIF-1α–p300 interface and suppresses hypoxia-driven signaling in ccRCC, supporting the use of transcriptional complex inhibition as a promising therapeutic strategy.

TGFBR3 regulates the expression of FATP2-ACSL1 axis related proteins and accompanies changes in the migration and invasion ability of lung cancer cells

Background Abnormal lipid metabolism promotes lung cancer progression. This study explores how TGFBR3 regulates fatty-acid-metabolism-related protein expression via the FATP2-ACSL1 axis to suppress lung cancer invasion and metastasis, and preliminarily assesses the potential clinical value of TGFBR3 and FATP2. Methods Serum samples were collected from 30 healthy individuals and 170 newly diagnosed lung cancer patients for lipid profiling. Network pharmacology, Mendelian randomization, molecular docking, co-immunoprecipitation (Co-IP) and GST-Pull down assay were used to validate the TGFBR3-FATP2 interaction. Stable cell lines were established to assess function and mechanism via CCK-8, wound healing, Transwell, and Western blotting. Serum levels of soluble TGFBR3 (sTGFBR3) and FATP2 were measured by ELISA. Results Serum CHOL, HDL-C, and LDL-C were significantly decreased in lung cancer patients (P < 0.05). Mendelian randomization indicated that elevated HDL-C reduces lung cancer risk (OR = 0.5607). Molecular docking showed a binding energy of −12.5 kcal/mol, Co-IP and GST-Pull down assay confirmed the interaction. TGFBR3 overexpression inhibited migration and invasion, while knockdown had the opposite effect (P < 0.05). TGFBR3 regulated FATP2, ACC1, ACSL1, and SCD1 expression but not CD36. Lipofermata reversed the protein changes induced by TGFBR3 knockdown. ELISA results showed that serum sTGFBR3 and FATP2 levels were significantly higher in lung cancer patients than in healthy and pneumonia controls (P < 0.05), and sTGFBR3 levels were higher in LUSC and SCLC than in LUAD (P < 0.05). The AUCs were 0.931 for sTGFBR3 and 0.998 for FATP2, showing higher diagnostic performance compared with CEA and other traditional markers in this cohort. Furthermore, sTGFBR3 levels decreased after carboplatin dose reduction or discontinuation and increased after treatment resumption; in vitro experiments confirmed that carboplatin upregulated TGFBR3 expression and promoted the release of its soluble form (P < 0.05). although this effect may be partly attributed to nonspecific cell injury. Conclusions TGFBR3 interacts with FATP2 and is associated with the regulation of migration and invasion in lung cancer cells, potentially involving the FATP2-ACSL1 axis. Additionally, serum levels of sTGFBR3 and FATP2 were identified as potential candidate biomarkers for lung cancer, warranting further validation in independent cohorts migration.