Obesity is closely associated with the initiation and progression of colorectal cancer (CRC) and is widely recognized as a risk factor for unfavorable surgical outcomes. Nevertheless, the extent to which visceral obesity specifically influences perioperative safety and long-term oncologic outcomes following CRC resection remains to be established. We performed a systematic review and meta-analysis by comprehensively searching PubMed, Web of Science, Embase, Scopus, and the Cochrane Library. Continuous, dichotomous, and survival-related variables were synthesized using weighted mean difference (MD) or standardized MD (SMD), odds ratios (ORs), and hazard ratios (HRs), respectively. A total of 23 studies comprising 6,500 patients were included. Relative to patients without visceral obesity, those with visceral obesity demonstrated significantly prolonged operative time, greater intraoperative blood loss, higher rates of conversion to open laparotomy, increased overall postoperative complication rates, higher incidences of incisional wound infection and anastomotic leakage, a reduced number of harvested lymph nodes, and extended postoperative hospital stay. In contrast, no statistically significant differences were identified in postoperative mortality, positive surgical margin rates, time to first flatus, urinary dysfunction, 5-year disease-free survival, or 5-year overall survival. Collectively, these findings indicate that visceral obesity substantially increases intraoperative technical difficulty and postoperative morbidity; however, it does not appear to compromise long-term oncologic outcomes following CRC resection.

Supplemental Table 2. List of antibodies used in this study, including sources and dilutions.

Correlation between Hnrnpa2b1-associated signatures and HNRNPA2B1 expression.

Flow cytometry analysis of the tumor immune microenvironment following Hnrnpa2b1 deletion.

FOLFOX has served as the standard chemotherapy regimen for advanced stages, specifically in the treatment of pancreatic, colorectal, and bladder cancers. However, the issues of excessive toxicity and prolonged treatment cycles persist. To address this limitation, we developed a novel methylated amino acid-modified lignin inspired by biological methylation, creating a pH-responsive charge-reversal drug delivery system for FOLFOX chemotherapy. This system stabilizes thymidylate synthase (TS) and combines with deoxyuridine monophosphate (dUMP) to demonstrate significantly improved therapeutic outcomes of FOLFOX against colorectal cancer (CRC). The FOLFOX-loaded nanodrug showed targeted antitumor activity against CRC and induced tumor cell death through multiple mechanisms, including apoptosis, necrosis, cell cycle regulation, DNA damage, and reactive oxygen species generation. Furthermore, the nano-formulation activated immune responses to enhance chemotherapeutic potency and effectively reducing renal toxicity associated with chemotherapy drugs. These findings suggest that protein methylation-mimicked lignin could be a valuable addition to current first-line chemotherapy options and holds promise for enhancing chemotherapy against solid tumors.

Background Colon cancer harboring TP53 mutations is highly aggressive and associated with short survival. Adaptive, rather than apoptotic, endoplasmic reticulum (ER) stress endows TP53-mutant tumor cells with enhanced protein-folding capacity, metabolic plasticity, and chemoresistance. However, the upstream regulators that selectively drive this cytoprotective program within the cancer stem cell compartment remain elusive. Methods Single-cell RNA-seq analysis of TP53-mutant versus wild-type tumors was performed to identify ER stress- and mitochondrial metabolism-related differentially expressed genes (EMRDEGs). A four-gene prognostic signature was constructed from TCGA-COAD and GEO cohorts using DESeq2 and LASSO regression. Functional analyses included gain- and loss-of-function studies in TP53-mutant (SW480, HT-29) and TP53-wild-type (HCT116) colon cancer cells, followed by CCK-8, colony formation, microsphere formation, xenograft, dual-luciferase reporter, coimmunoprecipitation and western blot assays. Results TP53-mutant tumor stem cells exhibited synchronized activation of ER stress and mitochondrial metabolic pathways, guiding EMRDEG selection. Among the signature genes, nucleolar protein 3 (NOL3) emerged as an independent adverse prognostic factor that correlated with advanced stage, nodal positivity and shorter overall survival. NOL3 enhanced proliferation and cancer stem cell properties in a TP53-mutant-dependent manner. Mechanistically, ELK1 transcriptionally upregulated NOL3, which physically interacted with GRP78 to activate the PERK/CHOP branch of the unfolded protein response, thereby amplifying adaptive ER stress. Conclusion The ELK1/NOL3/GRP78 axis promotes the progression of TP53-mutant colon cancer by increasing adaptive ER stress and stemness. NOL3 serves as a valuable prognostic biomarker and a potential therapeutic target.

Supplemental Table 7. Marker genes identified for each Seurat cluster in single-cell RNA-sequencing (scRNA-seq) data from subcutaneous tumor samples in mice.

Altered cellular interactions in the tumor microenvironment following Hnrnpa2b1 deletion.

The hepatic microenvironment undergoes dynamic remodelling in advanced liver fibrosis. Hyaluronic acid (HA), a key component of this fibrotic microenvironment, plays a key role in disease progression. While cellular senescence is one of the fates that activated HSCs undergo and is associated with fibrosis resolution, the relationship between HA and HSC senescence in advanced liver fibrosis remains unclear. This study aimed to elucidate the specific mechanisms by which HA regulates HSC senescence. Here, intrahepatic HSC transplantation confirmed that an advanced fibrotic microenvironment inhibited HSC senescence and led to its sustained activation. Mechanistically, low-molecular-weight (LMW) HA promotes HSC activation via the CD44-p38-ATF2 axis, while HMW-HA simultaneously inhibits HSC senescence through the TLR4-SerpinE1 axis. Furthermore, HA synthesis is mediated by MASP1. MASP1 enhances the m6A methylation of HAS2 via METTL3, leading to increased HAS2 mRNA levels and consequently elevated HMW-HA synthesis, and HYAL2 mediates the conversion of HMW‑HA to LMW‑HA. Targeted knockdown of MASP1 in the liver reversed HA metabolism, subsequently promoting HSC senescence and alleviating liver fibrosis. Therefore, targeting HA metabolism to induce HSC senescence for activated HSC removal may represent a novel therapeutic strategy for liver fibrosis.

Colorectal cancer (CRC) is a common malignancy and a leading cause of morbidity and mortality worldwide. Taurine, a sulfur-containing amino acid derivative, has gained attention for its potential regulatory role in CRC. In addition, active metabolites, such as hydrogen sulfide produced by the interaction between taurine and intestinal microbiota, may influence CRC progression. This review systematically examines the role of the “taurine-gut microbiota” axis in the pathogenesis and treatment of CRC. We summarize the mechanisms by which taurine inhibits tumor proliferation, induces apoptosis, and enhances chemosensitivity. We also highlight its role in modulating the tumor immune microenvironment, maintaining intestinal barrier function, and preserving microbial homeostasis through microbiota-mediated metabolic regulation. Finally, we discuss translational strategies, including dietary interventions and taurine-based combination therapies, providing a new perspective for integrating taurine into CRC management.

Background Chronic inflammation and elevated reactive oxygen species are key contributors to hepatocellular carcinoma (HCC) progression. Objective This study aims to investigate the role of the oxidative stress sensor protein Pirin (PIR) as a critical mediator of inflammation in HCC progression. Design We investigated PIR’s role in HCC tumourigenesis through RNA interference, genetic knockout and pharmaceutical inhibition in HCC cell lines and various mouse models. Furthermore, we used transcriptomics, quantitative reverse transcription PCR, western blot, immunofluorescence staining and immunohistochemistry analysis to elucidate the molecular details. Results This study reveals a novel redox-dependent mechanism governing PIR’s nuclear shuttling, contributing to liver inflammation and HCC progression. We identified a positive feedback axis where nuclear PIR amplifies inflammatory responses, leading to hepatitis and HCC advancement. Cytokines in this loop are regulated by PIR-enhanced v-rel reticuloendotheliosis viral oncogene homolog A (RELA) transcription, promoting PIR’s nuclear translocation, increasing proinflammatory cytokine levels, and disrupting redox balance. We confirmed that liver parenchymal cells produce autocrine cytokines supporting their growth and malignancy. Notably, PIR’s redox-mediated nuclear shift can be inhibited by N-acetyl cysteine or PIR inhibitors, reducing HCC promotion in mice. Conclusion We elucidate a novel redox-dependent regulatory mechanism governing the nuclear localisation of PIR and its role in promoting liver inflammation and HCC progression. Our findings underscore the significance of cellular redox status in regulating PIR’s activity and highlight the potential of targeting this pathway with antioxidants to mitigate HCC progression.

Mechanistic analysis of HNRNPA2B1-mediated regulation of interferon signaling and CD8⁺ T cell responses.

Supplemental Table 1. List of reagents and resources used in this study.

Immune checkpoint blockade (ICB) has transformed colorectal cancer therapy, yet the majority of microsatellite-stable colorectal cancers remain refractory because of insufficient tumor-immune cell cross-talk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. In this study, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in colorectal cancer, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a noninflamed ("cold") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized microsatellite-stable colorectal cancers to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1's impact on tumor-immune interactions, and it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in colorectal cancer.

Single-cell transcriptomic profiling of immune cell subsets in Hnrnpa2b1-deficient tumors.

Supplemental Table 6. Degree centrality values for upregulated RNA-binding proteins in the protein–protein interaction network.

Clinical and biological characteristics associated with the Hnrnpa2b1 interaction signature in CRC.

Supplemental Table 17. Gene signatures correlated with CD8+ T-cell activation states.

Supplemental Table 8. Mean expression values of marker genes delineating major cell types in the scRNA-seq dataset of subcutaneous tumors in mice.