Background: The expression levels of the programmed death-ligand 1 (PD-L1) protein serves as a prognostic indicator for patients with colorectal cancer (CRC). Advancement of CRC is facilitated by deubiquitinating enzymes (DUBs), which regulate oncoprotein levels via the ubiquitin-proteasomal pathway. The post-translational regulatory mechanisms governing PD-L1 protein abundance on CRC, in relation to different tumor grades and their clinical relevance, remains unknown. Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data to identify DUB genes associated with PD-L1 expression in CRC. We used a loss-of-function-based CRISPR/Cas9 library to identify putative DUB genes that regulate the PD-L1 protein level. Immunoprecipitation was used to confirm the interaction between the USP32 and PD-L1 along with its ubiquitination status. A series of in vitro and in vivo carcinogenesis-related experiments were conducted to determine the clinical relevance between USP32 and PD-L1 expression in CRC progression. Results: In this study, we analyzed scRNA-seq data from extensive cohorts of human and mice at the single-cell level to identify DUB genes associated with PD-L1 expression in CRC. Our analysis identified multiple putative DUBs, including USP32 and USP12, as prognostic markers associated with PD-L1 expression, which was found to be elevated in T cells, macrophages, and classical monocytes cell types in patients with CRC. A secondary screening using CRISPR/Cas9-mediated loss-of-function analysis for DUBs found that USP32 modulates PD-L1 protein levels in CRC. Furthermore, we demonstrated that USP32 interacts with, stabilizes, and extends the half-life of PD-L1 by preventing its K-48-linked polyubiquitination as an underlying mechanism that contributes for tumorigenesis. Conclusion: A combination of scRNA-seq analysis and wet-lab experimental validation confirmed that USP32 mediates PD-L1 protein stabilization in colon cancer, identifying it as a potential therapeutic target for CRC. CRISPR/Cas9-mediated targeted knockout of the USP32 gene reduced PD-L1 protein levels and significantly mitigated colorectal cell proliferation and tumorigenesis, both in vitro and in vivo, in a xenograft mouse model, underscoring a novel and alternative approach to the treatment of CRC.

Understanding the relationship between surgical specialisation and outcomes following emergency surgery for colorectal cancer - a retrospective population-based study in the English NHS.

M1-like tumor-associated macrophages promote colorectal cancer progression through feedback activation of the IL1β/NF-κB signaling activity.

MIF/CD74/CD44 pathway communicates between macrophages and colorectal Cancer cells and predicts survival of patients.

E3 ubiquitin ligase WSB1-mediated ubiquitination modification of DIO2 promotes colorectal cancer stemness and metastasis by blocking thyroid hormone signaling.

Clinicopathological features and mutational landscape of colorectal cancer subgroups defined by MSI and EMAST status.

Integrated activity-guided isolation and transcriptomic analysis reveal the therapeutic mechanism of Thonningianin A from Penthhorum chinense Pursh against colorectal cancer via p21 modulation.

Bacterial extracellular vesicle ssRNA prevents colorectal cancer progression via Piezo1.

Direct MS enabled discovery of lipid signatures with diagnostic implications in colorectal cancer.

Leucine‑rich repeat‑containing protein 59 (LRRC59), a 244‑amino‑acid endoplasmic reticulum membrane protein, is implicated in the tumorigenesis of multiple malignancies. However, its functional significance in colorectal cancer (CRC) remains poorly understood. In the present study, LRRC59 expression in CRC tissues was evaluated using immunohistochemistry and western blotting. Colony formation, Cell Counting Kit‑8, wound healing and Transwell assays, in in vivo xenograft models, were used to evaluate the effect of LRRC59 on CRC progression. Apoptosis was analyzed using flow cytometry and western blotting. The interaction between LRRC59 and the protein kinase RNA‑like endoplasmic reticulum kinase (PERK) pathway was verified using the starBase database and western blotting. It was found that LRRC59 expression was significantly higher in CRC tissues than in normal tissues. LRRC59 knockdown in HCT116 and LoVo cells inhibited proliferation, migration and invasion and promoted apoptosis, and the PERK pathway was significantly activated. In vivo subcutaneous tumorigenesis assays corroborated these in vitro findings. Treatment with a PERK pathway‑specific inhibitor reduced the apoptosis of HCT116 and LoVo cells with LRRC59 knockdown. These findings suggest that LRRC59 is not only significantly upregulated in CRC but also mechanistically drives tumor progression by coordinating pro‑oncogenic processes, including enhanced proliferation, migration and invasion. Importantly, mechanistic evidence was provided that LRRC59 inhibits apoptosis by suppressing the PERK signaling axis, identifying this molecule a target in the development of CRC therapeutic strategies.

Advanced oral therapies for colorectal cancer via nanomedicine and microbiota modulation.

CDS1 deficiency promotes colorectal cancer progression by suppressing CDP-DAG-induced ferroptosis in MDSCs.

Hedyotis diffusa willd-scutellaria barbata herbal Pair ameliorates colitis-associated colorectal cancer progression by modulating the gut microbiota and the PPARγ/NF-κB pathway.

Single-cell transcriptome profiling of post-treatment and treatment-naïve colorectal cancer: Insights into putative mechanisms of chemoresistance.

RNA-binding protein GIGYF2 promotes colorectal cancer progression through activation of the METTL3/SERP1/STAT3 axis in an m6A-IGF2BP2-dependent manner.

Background: Oxaliplatin resistance poses a significant therapeutic challenge in colorectal cancer (CRC), contributing to disease progression and poor clinical outcomes. There is an urgent need to identify novel molecular targets to overcome chemoresistance and inhibit metastatic dissemination. Methods: We conducted integrative multi-omics analyses to identify genes associated with oxaliplatin resistance in CRC and detected ARL4C, a small GTPase, as a candidate driver. Functional experiments, including gene knockdown/overexpression, mutant construction, cell viability, apoptosis, migration, and invasion assays, as well as in vivo mouse models, were used to evaluate the role of ARL4C. Signaling pathways were examined using proteomics and molecular biology techniques. We employed network pharmacology and molecular docking to identify ARL4C-targeting compounds and selected β-Lapachone for further validation. Results: ARL4C was significantly overexpressed in oxaliplatin-resistant CRC tissues and correlated with poor prognosis and increased metastatic potential. Mechanistic studies revealed that ARL4C activates RAP1/PI3K-Akt-mTOR and RAC1/Arp2/3 signaling axes, promoting cell survival, epithelial-mesenchymal transition, and invasion. ARL4C also inhibited its own ubiquitination by regulating USP38, forming a positive feedback loop that enhanced protein stability following chemotherapy. β-Lapachone was identified as a direct ARL4C inhibitor that binds competitively at the LYS128 residue, disrupting USP38 interactions and promoting ARL4C degradation. Combination therapy with β-Lapachone and oxaliplatin significantly suppressed tumor growth, reduced metastasis, reversed drug resistance, and mitigated oxaliplatin-induced renal toxicity in preclinical models. Conclusions: Our study identifies ARL4C as a critical mediator of chemoresistance and metastasis in CRC. Targeting ARL4C with β-Lapachone restores oxaliplatin sensitivity and enhances therapeutic efficacy, offering a promising combinatorial strategy with strong potential for clinical translation in drug-resistant CRC.

ROS-mediated senescence and autophagy inhibition drive 5-FU/Aumolertinib synergy in colorectal cancer.

Simple porphyrin nanoparticles for combined photo-immunotherapy of colorectal cancer.

Exploring the mechanisms of WeifuChun in colorectal cancer: Network pharmacology-based identification and experimental validation of key signaling pathways.

High-fat diet promotes colorectal tumorigenesis through gut microbiota-mediated metabolic reprogramming and M2 macrophage polarization.