Jingxin Li

Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal Bacteroides ovatus, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K-HIF1α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient B. ovatus mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type B. ovatus markedly reduces tumor burden. These findings identify a microbiota-neurotransmitter-metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.

Distant metastasis, predominantly to the liver, remains the leading cause of death in colorectal cancer (CRC), yet biomarkers that capture metastatic competence remain limited. Ferroptosis is an iron‐dependent, lipid peroxidation‐driven form of regulated cell death that can restrain tumor progression, but whether primary CRC from patients with liver metastasis shows ferroptosis‐resistance‐related features remains incompletely understood. In a small exploratory set of T‐stage‐matched primary CRC tumors with or without liver metastasis, we quantified glutathione redox and lipid peroxidation‐related readouts and assessed SLC7A11 and GPX4 expression. We integrated GSE62321 transcriptomic profiles with a FerrDb ferroptosis gene set, evaluated prognosis in TCGA‐COAD/READ, and performed genetic knockdown, MDA assays, C11‐BODIPY lipid ROS staining, ferrostatin‐1 rescue assays, and Transwell assays in CRC cell models. Primary tumors from patients with liver metastasis showed a more reduced redox profile and increased expression of core ferroptosis‐suppressive proteins, consistent with enhanced ferroptosis resistance potential but not direct evidence of lower in vivo ferroptotic cell death. Integrative discovery highlighted fatty acid binding protein 4 (FABP4), α‐synuclein (SNCA), and discoidin domain receptor 2 (DDR2) as CRC‐LM‐associated ferroptosis‐related candidates. High expression of each gene was associated with unfavorable disease‐free survival. In CRC cell models, including the lymph‐node‐metastasis‐derived SW620 line and additional validation lines, silencing FABP4, SNCA, or DDR2 increased bulk MDA and/or C11‐BODIPY‐detected lipid ROS, altered ferroptosis susceptibility, and suppressed migratory and/or invasive phenotypes. Ferrostatin‐1 partially rescued knockdown‐induced viability loss, lipid ROS accumulation, and migratory/invasive defects, supporting involvement of ferroptosis‐associated lipid peroxidation while not excluding broader stress‐response mechanisms. FABP4, SNCA, and DDR2 are CRC‐LM‐associated ferroptosis‐related candidates that modulate lipid peroxidation, ferroptosis susceptibility, and migratory/invasive phenotypes in CRC cell models, warranting further validation in viability‐controlled and liver metastasis‐specific models.

Slow‐transit constipation (STC) is a disabling motility disorder with unclear smooth‐muscle mechanisms. Through spatial proteomics of human colon and functional assays in primary human colonic smooth muscle cells (HCoSMCs), we identified Bridging Integrator 1 (BIN1) and Aldehyde Dehydrogenase 1B1 (ALDH1B1) as key regulators of intestinal motility. Both proteins were markedly reduced in smooth muscle from STC patients and localized to fibrotic areas. Lentiviral knockdown of BIN1 or ALDH1B1 impaired ATP‐evoked Ca ^{2 +} responses and contraction, disrupted mitochondrial architecture, and increased reactive oxygen species. BIN1 deficiency activated mitochondrial apoptosis and extracellular matrix deposition, whereas ALDH1B1 loss induced mitophagy and NF‐κB–driven inflammation. Transcriptomic and histological analyses confirmed convergence on profibrotic pathways. Together, these findings reveal a smooth‐muscle‐centric mechanism underlying STC pathogenesis and nominate BIN1 and ALDH1B1 as promising therapeutic entry points to restore intestinal motility.

Zhang D-L, Sun Y-J, Ma M-L, Wang Y-, Lin H, Li R-R, Liang Z-L, Gao Y, Yang Z, He D-F, Lin A, Mo H, Lu Y-J, Li M-J, Kong W, Chung KY, Yi F, Li J-Y, Qin Y-Y, Li J, Thomsen ARB, Kahsai AW, Chen Z-J, Xu Z-G, Liu M, Li D, Yu X, Sun J-P. 2018. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. eLife 7:e33432. doi: 10.7554/eLife.33432.

Vitamin B ₆ is implicated in multiple mental disorders, and accumulating evidence suggests an inverse relationship with depression; however, important aspects of the underlying dose–response patterns and the roles of individual circulating vitamin B ₆ metabolites remain incompletely understood. We analysed data from the National Health and Nutrition Examination Survey 2005–2010. Depression was defined as a Patient Health Questionnaire-9 score ≥10. Vitamin B ₆ status was assessed using serum pyridoxal 5′-phosphate (PLP), the biologically active coenzyme form, and 4-pyridoxic acid (PA), the principal catabolic and urinary excretion product of vitamin B ₆ . Among 12 620 participants, 1070 (8·5 %) met criteria for depression. After adjusting for relevant covariates, multiple logistic regression revealed that individuals in higher quartiles of serum PLP and PA (Q2–Q4) had significantly lower odds of depression compared with those in the lowest quartile (Q1). Restricted cubic spline analyses identified nonlinear relationships: L-shaped for PLP (P-nonlinearity = 0·001) and U-shaped for PA (P-nonlinearity = 0·017). Below the inflection points (90·7 nmol/L for PLP; 73·9 nmol/L for PA), both metabolites showed significant inverse associations with depression (PLP: OR = 0·992, 95 % CI: 0·988–0·996, P < 0·001; PA: OR = 0·994, 95 % CI: 0·993–0·996, P < 0·001). Above these thresholds, the association became non-significant for PLP ( P = 0·353), while PA demonstrated a positive association with depression (OR = 1·008, 95 % CI: 1·002–1·013, P < 0·01). Subgroup analyses confirmed the robustness of these inverse associations across demographic categories. Serum vitamin B ₆ metabolites, PLP and its excretion product PA, exhibit non-linear associations with depression, with distinct threshold effects and metabolite-specific patterns that likely reflect both vitamin B ₆ availability and turnover.

Gastric cancer (GC) remains a significant global health challenge, often diagnosed at advanced stages due to the absence of reliable early detection biomarkers. In this study, we collected serum samples from multicenter, demonstrating elevated serum levels of LINC 02086 exhibit high diagnostic accuracy. LINC 02086 significantly upregulated in GC tissues, with its expression correlating with poor patient survival. As a driving factor of GC, Helicobacter pylori infection upregulates LINC 02086. Mechanistically, we found METTL3-mediated N6-methyladenosine modification of LINC 02086 promotes GC progression, which upregulates HuR by sponging miRNA-139. We also explored the therapeutic potential of LINC 02086-targeted siRNA delivered via lipid nanoparticles, showing significant inhibition of GC growth and metastasis. These findings position LINC 02086 as a promising serum biomarker for early GC detection and as a potential therapeutic target, paving the way for improved diagnostic and treatment strategies in GC.