The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg–nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg–urea (catalyzed by arginases) pathways in IBD are debatable; the Arg–polyamine and Arg–creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration.

The role of tumor-associated macrophages (TAMs) along with the regulatory mechanisms underlying distinct macrophage activation states remain poorly understood in prostate cancer (PCa). Herein, we reported that PCa growth in macrophage-specific Ubc9 deficient mice is substantially suppressed compared to their wild-type littermates, an effect partially ascribed to the augmented CD8⁺ T cell response. Biochemical and molecular analyses revealed that the signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of UBC9 inhibitor, 2-D08, promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8⁺ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade (ICB) therapy. Together, our results demonstrated that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs via promoting STAT4 mediated macrophage activation and macrophage-CD8⁺ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

Inflammatory bowel disease (IBD) is a chronic autoimmune disorder stemming from unrestrained immune activation and subsequent destruction of colon tissue. Genetic susceptibility, microbiota remodeling, and environmental cues are involved in IBD pathogenesis. Up to now, there are limited treatment options for IBD, so better therapies for IBD are eagerly needed. The therapeutic effects of naturally occurring compounds have been extensively investigated, among which quercetin becomes an attractive candidate owing to its unique biochemical properties. To facilitate the clinical translation of quercetin, we aimed to get a comprehensive understanding of the cellular and molecular mechanisms underlying the anti-IBD role of quercetin. We summarized that quercetin exerts the anti-IBD effect through consolidating the intestinal mucosal barrier, enhancing the diversity of colonic microbiota, restoring local immune homeostasis, and restraining the oxidative stress response. We also delineated the effect of quercetin on gut microbiome and discussed the potential side effects of quercetin administration. Besides, quercetin could serve as a prodrug, and the bioavailability of quercetin is improved through chemical modifications or the utilization of effective drug delivery systems. Altogether, these lines of evidence hint the feasibility of quercetin as a candidate compound for IBD treatment.

Colitis is a major form of inflammatory bowel disease which involved mucosal immune dysfunction. Aloperine is an alkaloid isolated from the shrub Sophora alopecuroides L. and has been recognized as an effective treatment for inflammatory and allergic diseases. The present study aimed to examine the molecular mechanisms underlying aloperine-mediated colitis protection. We found that aloperine treatment improved colitis induced by dextran sodium sulfate (DSS) based on body weight, disease activity index, colonic length, and spleen index. Aloperine also effectively attenuated DSS-induced intestinal inflammation based on the pathological score and myeloperoxidase expression and activity in colon tissues. In addition, aloperine regulated T-cell proportions and promoted Foxp3 expression in the spleens and mesenteric lymph nodes of DSS-induced colitis mice and in the spleens of the Foxp3^GFP mice. Aloperine inhibited Jurkat and mouse naïve T-cell apoptosis. Furthermore, aloperine inhibited PI3K/Akt/mTOR signaling and upregulated PP2A expression in the DSS-induced colitis mice and in Jurkat cells, but LB-100 (PP2A inhibitor) resulted in an elevated Akt activity in Jurkat cells, activated T-cells, and human splenic mononuclear cells. Aloperine inhibited T-cell and lymphocyte proliferation, but LB-100 reverse these effects. In conclusion, aloperine regulates inflammatory responses in colitis by inhibiting the PI3K/Akt/mTOR signaling in a PP2A-dependent manner.

Macrophages are widely distributed in various tissues and organs. They not only participate in the regulation of innate and adaptive immune response, but also play an important role in tissue homeostasis. Dysregulation of macrophage function is closely related to the initiation, development and prognosis of multiple diseases, including infection and tumorigenesis. Forkhead box transcription factor O1 (FoxO1) is an important member among the forkhead box transcription factor family. Through directly binding to the promoter regions of downstream target genes, FoxO1 is implicated in cell proliferation, apoptosis, metabolic activities and other biological processes. In this review, we summarized the regulatory role of FoxO1 in macrophage phagocytosis, migration, differentiation and inflammatory activation. We also emphasized that macrophage reciprocally modulated FoxO1 activity via a post‐translational modification (PTM) dominant manner.

Colorectal cancer is a heterogeneous disease that develops through a stepwise accumulation, yet the underlying mechanisms at single-cell resolution remain unclear. In this study, we profiled 751,531 single-cell transcriptomes, spatial transcriptomics, and snMultiomes from 142 multistage samples, revealing the cellular and molecular alterations and dynamic intercellular cross-talk during colorectal cancer development. Additionally, we created a colorectal cancer single-cell expression quantitative trait locus (sc-eQTL) map identifying 16,833 significant pairs across 28 cell subtypes, with more than 76% of sc-eQTLs being cell type–specific and fewer than 15% detectable in bulk datasets. A polygenic risk score derived from sc-eQTLs substantially improved colorectal cancer risk prediction. We prioritized rs4794979 that is associated with an increased colorectal cancer risk (OR = 1.11, P = 2.04 × 10−12) by promoting LGALS9 expression mediated by ELK1. Elevated LGALS9 in epithelia interacts with SLC1A5 on fibroblasts, promoting transformation into cancer-associated fibroblasts and simultaneously inducing CD8+ T-cell exhaustion via the LGALS9–TIM3 axis, thereby facilitating colorectal cancer development. Blocking the LGALS9–TIM3 axis enhanced anti–PD-1 therapy to inhibit colorectal cancer progression. Significance: Our study provides a valuable resource, including a dynamic single-cell landscape and a robust colorectal cancer sc-eQTL atlas, and elucidates the cell type–specific regulation and important cross-talk mechanisms between cell types in the tumor microenvironment, offering deep insights into colorectal cancer tumorigenesis and targeted therapies.