TRAPPC4 knockout suppresses EMT and matrix remodeling associated gene expression.

PTV-mediated ferroptosis sensitization is largely dependent on TRAPPC4 in HNSCC cell and xenograft models.

Ischemic heart disease and related sequelae pose tremendous burdens on worldwide medical care. The excessive activation of cardiomyocytes and cardiac fibroblasts further exacerbates the prognosis after necrosis. Decades of stem cell therapy in preclinical studies suggested promising results in cardiomyocyte regeneration and tissue remodeling. However, few formulations achieved clinical translation due to the limited stem cell engraftment and insufficient arousal of resident cardiomyocytes. Here, we reported an implantable electroactive device to leverage stem cell therapy and cardiomyocyte restoration for effective heart recovery. Assisted by the piezoelectric microneedle patch with 80-cubic millimeter cavity, 1.5 × 105 mesenchymal stem cells could be delivered efficiently to the infarcted site and sustained longer for continuous paracrine effects. Meanwhile, the piezoelectric stimulation generated from the poly(l-lactic) acid microneedle matrix further potentiated the stem cells and elicited more vigorous self-repair responses in cardiomyocytes. This approach was validated to effectively suppress inflammatory monocytes, reduce cardiomyocyte necrosis, and improve heart remodeling in a rat heart infarction model.

OBJECTIVE:To investigate the molecular mechanisms of lipid metabolic reprogramming promoting tyrosine kinase inhibitors (TKIs) resistance in renal cell carcinoma (RCC). METHODS:To establish a sunitinib resistant renal cell carcinoma cell line (786O-R) and screen out arachidonic acid 5-lipoxygenase (ALOX5), a key gene regulating lipid metabolism, by transcriptome sequencing. To explore the expression of ALOX5 in TKI-resistant RCC tissues and cells, and the relationship between ALOX5 expression and the prognosis of RCC patients through databases and clinical samples. To explore the effect of ALOX5 on the malignant biological behavior of RCC cells and drug resistance to sunitinib in vitro. Transcriptome sequencing and molecular experiments were performed to explore the molecular mechanism of ALOX5 regulating lipid metabolism. The effect of ALOX5 inhibition on the tumorigenesis of 786O-R cell was investigated by animal experiments. RESULTS:ALOX5 is upregulated in TKI-resistant RCC tissues and cells. High ALOX5 expression is associated with poor prognosis of patients with RCC. Overexpression of ALOX5 can enhance the proliferation, migration, invasion and sunitinib resistance of 786O-R cell. ALOX5 promotes sunitinib resistance in 786O-R cell by regulating lipid metabolism through the p38/ERK/PPARα/CPT1A pathway. Inhibition of ALOX5 inhibited the growth of subcutaneous tumors and lung metastases in 786O-R cell. CONCLUSION:ALOX5 mediates sunitinib resistance in RCC by promoting lipid metabolism through the p38/ERK/PPARα/CPT1A pathway. Inhibition of ALOX5 may be a potential therapeutic target for intervention of metabolic abnormalities and overcoming resistance to targeted therapy in RCC.

The regulatory effects of FOS on TRIM55 and GPX4 are dependent on TRAPPC4 status.

BACKGROUND:Sepsis is a major cause of death in cancer patients, yet its variation by cancer type and patient characteristics remains underexplored. We analyzed sepsis mortality in a large cancer cohort, focusing on gender and demographic disparities. METHODS:We analyzed 3 577 100 cancer cases from the SEER database (1975-2019) and calculated the standardized mortality ratio (SMR) and absolute excess risk (AER), stratified by gender, cancer type, and demographics. Logistic regression identified factors linked to sepsis mortality odds, while Cox proportional hazards models evaluated their time-dependent effects. RESULTS:Cancer patients experienced an excess sepsis mortality rate of 1.68 deaths per 10 000 person-years compared to the general population. Among 11 926 cancer patients who died from sepsis (0.39% of 3.07 million cases), males had consistently higher mortality than females. Risk was highest in older adults, Black, unmarried, or widowed males with high-grade cancer. Liver and pancreatic cancers showed the highest SMR and AER, followed by stomach, lung, and hematologic cancers, whereas breast and prostate cancers had lower mortality. Patients diagnosed within the first year of cancer diagnosis faced the greatest risk. Logistic regression identified protective factors including female sex, younger age, localized cancer, marriage, and radiation therapy, while Cox models highlighted the time-dependent protective effects of these factors. CONCLUSIONS:Sepsis mortality varied significantly by gender, cancer type, and demographic characteristics. These findings emphasize the need for gender-specific and personalized management strategies to reduce sepsis mortality in high-risk cancer patients.

Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive progression, frequent therapeutic resistance, and poor clinical outcomes. Although the RNA-binding protein La/SSB is aberrantly expressed in multiple malignancies, its functional and mechanistic role in HNSCC remains incompletely understood. Here, by integrating transcriptomic and chromatin accessibility profiling with comprehensive in vitro and in vivo analyses, we identify La/SSB as a putative regulator associated with HNSCC progression and cisplatin (CDDP) resistance. La/SSB was markedly upregulated in HNSCC tissues and cell lines, and elevated expression was associated with unfavorable survival. Genetic depletion of La/SSB suppressed proliferation, migration, and invasion, promoted apoptosis, and reduced tumor growth and metastatic colonization, whereas ectopic expression exerted the opposite effects. Multi-omics analyses implicated FSCN1 as a functionally relevant downstream candidate associated with La/SSB-dependent phenotypes. Mechanistically, La/SSB depletion was associated with reduced H3K27ac enrichment and diminished TFAP2C occupancy at the FSCN1 promoter, supporting a TFAP2C/FSCN1-linked regulatory framework. Importantly, loss of La/SSB significantly enhanced CDDP responsiveness in the PDO model established in this study and in vivo conditional knockout models. Clinically, elevated La/SSB showed independent prognostic value, whereas TFAP2C and FSCN1 supported a biologically associated regulatory framework linked to aggressive disease features. Collectively, our findings identify La/SSB as a clinically relevant factor associated with HNSCC progression and CDDP responsiveness, and support a TFAP2C/FSCN1-linked regulatory framework that may contribute to malignant phenotypes.

Silencing GPX4 in TRAPPC4-overexpressing TU177 cells reversed their resistance to ferroptosis.

PTV sensitizes HNSCC to ferroptosis and cooperates with RSL3 to suppress tumor progression.

Abstract Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages, resulting in poor clinical outcomes. Ferroptosis resistance presents a major challenge in the treatment of HNSCC, highlighting the need to elucidate the mechanisms that enable HNSCC cells to evade ferroptosis. In this study, we conducted a genome-wide CRISPR–Cas9 knockout screen and identified trafficking protein particle complex subunit 4 (TRAPPC4) as a key regulator of ferroptosis resistance in HNSCC. Across a comprehensive set of experimental models, including HNSCC cell lines, patient-derived organoids, cell-derived xenografts, patient-derived xenografts, Trappc4 conditional knockout mice, and lymph node and lung metastasis models, TRAPPC4 promoted tumor progression by inhibiting ferroptosis. Mechanistically, TRAPPC4 decreased chromatin accessibility at a distal regulatory element upstream of TRIM55, thereby limiting FOS-dependent transcription. This repression reduced TRIM55-mediated GPX4 ubiquitination and degradation, resulting in GPX4 stabilization and ferroptosis resistance. Structure-based high-throughput virtual screening identified pitavastatin (PTV) calcium as a TRAPPC4-binding compound that promoted TRAPPC4 degradation. Notably, PTV calcium synergized with the ferroptosis inducer RSL3 to enhance ferroptotic activity and suppress HNSCC progression. These findings delineate a TRAPPC4–FOS–TRIM55–GPX4 signaling axis that drives ferroptosis resistance and tumor progression and highlight TRAPPC4 as a promising therapeutic target for ferroptosis-based intervention in HNSCC. Significance: TRAPPC4 enables head and neck squamous cell carcinoma to resist ferroptosis by regulating TRIM55-mediated GPX4 degradation, providing a potential therapeutic target to inhibit cancer progression.

Prostate cancer (PCa) is one of the most common cancers in males, and its treatment remains challenging due to the tumor microenvironment (TME) with immunosuppressive properties and limited response to anti-PD-1 therapy. Gut microbiota-derived metabolites have recently emerged as modulators of cancer immunometabolism, however, their role in PCa progression and immunotherapy is poorly understood. Here we found that indole-3-lactic acid (ILA), a metabolite produced by Lactobacillus plantarum, exerted dual anti-tumor effects on PCa cells and the TME. Mechanistically, ILA activates the aryl hydrocarbon receptor (AHR), and the resulting AHR/ARNT heterodimer translocates into the nucleus and binds to the promoter of ASF1B. This heterodimer then recruits the HDAC1/2-NuRD complex to reduce H3K27ac levels and suppress ASF1B expression. ASF1B binds to specific residues of ENO1 via its N-terminal core domain and enhances ENO1 enzymatic activity. ILA-induced downregulation of ASF1B impairs this interaction, reduces ENO1 activity, and suppresses the PI3K/Akt pathway, thereby inhibiting the malignant phenotypes of PCa cells. Concurrently, ILA decreased CXCL8 secretion by inhibiting the PI3K/Akt/NF-κB pathway, enhancing CD8+ T cell infiltration and M1 macrophage polarization, thereby remodeling the TME. Additionally, ILA synergized with anti-PD-1 therapy to more effectively suppress tumor growth. These findings reveal a novel mechanism by which gut microbiota-derived metabolites regulate PCa progression and immunometabolism, positioning ILA as a potential therapeutic agent to improve PCa treatment.

Pseudomonas aeruginosa infection is still a serious problem among immunocompromised patients who have advanced urinary tract malignancies, yet the impact of P. aeruginosa on disease progression remains poorly defined. In this study, we show that urinary tract infections caused by P. aeruginosa exacerbated bladder cancer progression in murine models, primarily by inducing an immunosuppressive tumor microenvironment. Mechanistically, P. aeruginosa activated Toll-like receptor 5 (TLR5) on bladder cancer cells, triggering phosphorylation of ERK1/2 and subsequent secretion of the chemokine CCL20. This signaling axis promoted the recruitment of myeloid-derived suppressor cells (MDSC), thereby reinforcing immunosuppression within the tumor microenvironment and exacerbating bladder cancer growth. In clinical samples, 16S rRNA sequencing and transcriptome analysis of bladder cancer tissues confirmed the presence of P. aeruginosa, with its abundance significantly correlating with advanced disease stages and elevated CCL20 expression. Collectively, these data identify a role for P. aeruginosa in promoting bladder cancer progression through TLR5-ERK1/2-CCL20-mediated MDSC recruitment, shedding light on the intricate interplay between microbial infection and cancer pathogenesis. These insights highlight potential therapeutic targets to disrupt infection-driven cancer progression.

TRAPPC4 knockout accelerates GPX4 protein degradation.

Integrated multi-omics analyses identify TRAPPC4 (TRA) as a prioritized candidate associated with ferroptosis resistance in HNSCC.

Identification of ETV5 as an upstream transcriptional activator of TRAPPC4 in HNSCC.

MID1 mediates the TRAPPC4-driven enhancement of proliferation, migration, and invasion in HNSCC.

Objective To investigate the molecular mechanisms of lipid metabolic reprogramming promoting tyrosine kinase inhibitors (TKIs) resistance in renal cell carcinoma (RCC). Methods To establish a sunitinib resistant renal cell carcinoma cell line (786O-R) and screen out arachidonic acid 5-lipoxygenase (ALOX5), a key gene regulating lipid metabolism, by transcriptome sequencing. To explore the expression of ALOX5 in TKI-resistant RCC tissues and cells, and the relationship between ALOX5 expression and the prognosis of RCC patients through databases and clinical samples. To explore the effect of ALOX5 on the nausea biological behavior of RCC cells and drug resistance to sunitinib in vitro. Transcriptome sequencing and molecular experiments were performed to explore the molecular mechanism of ALOX5 regulating lipid metabolism. The effect of ALOX5 inhibition on the tumorigenesis of 786O-R cells was investigated by animal experiments. Results ALOX5 is upregulated in TKI-resistant RCC tissues and cells. High ALOX5 expression is associated with poor prognosis of patients with RCC. Overexpression of ALOX5 can enhance the proliferation, migration, invasion and sunitinib resistance of 786O-R cell. ALOX5 promotes sunitinib resistance in 786O-R cell by regulating lipid metabolism through the p38/ERK/PPARα pathway. Inhibition of ALOX5 inhibited the growth of subcutaneous tumors and lung metastases in 786O-R cell. Conclusion ALOX5 promotes sunitinib resistance in RCC by promoting lipid metabolism through the p38/ERK/PPARα pathway. Inhibition of ALOX5 may be a potential therapeutic target for intervention of metabolic abnormalities and overcoming resistance to targeted therapy in RCC.

Overexpression of TRAPPC4 confers resistance to RSL3 induced ferroptosis in PDO models.

Bladder cancer cells recruit MDSCs during P. aeruginosa infection