Journal of Gastroenterology最新文献

{"title":"Evolving landscape of potassium-competitive acid blockers: toward disease-specific use beyond acid suppression.","authors":"Hideki Mori, Hidekazu Suzuki","doi":"10.1007/s00535-026-02422-4","DOIUrl":"10.1007/s00535-026-02422-4","url":null,"abstract":"<p><p>Potassium-competitive acid blockers (P-CABs) represent a major advancement in acid suppression by achieving rapid and sustained inhibition of gastric acid secretion. However, stronger acid suppression does not necessarily lead to better clinical outcomes. The clinical benefits of P-CABs vary according to the disease. In gastroesophageal reflux disease, P-CABs achieve healing rates for erosive esophagitis that are comparable to those of proton pump inhibitors (PPIs), with possible advantages in severe cases; however, consistent superiority in symptom control is lacking. The evidence for functional dyspepsia also remains insufficient. By contrast, in Helicobacter pylori eradication, P-CAB-based regimens have demonstrated clear advantages, particularly in the presence of antibiotic resistance. In peptic ulcer disease, the efficacy of P-CABs is comparable to that of PPIs. Long-term safety, including the effects of sustained hypergastrinemia, remains uncertain. Furthermore, symptom improvement and mucosal healing are not always concordant, thus highlighting the need to define therapeutic goals. Therefore, P-CABs should be used selectively on the basis of disease-specific requirements rather than pharmacological potency alone. An individualized approach is essential to optimize outcomes and avoid the unnecessary escalation of acid-suppressive therapy.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1187-1206"},"PeriodicalIF":5.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147973015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting METTL3 synergizes with Notch blockade to treat ESCC by targeting cancer stemness via m6A-JAG2.","authors":"Jingjing Duan, Yingying Jin, Yue Chen, Yinghui Shi, Haotian Wang, Ming Bai, Feixue Wang, Yuchong Yang, Shaohua Ge, Min Zhu, Yi Ba, Zhongyi Fan, Ting Deng","doi":"10.1007/s00535-026-02456-8","DOIUrl":"10.1007/s00535-026-02456-8","url":null,"abstract":"<p><strong>Background: </strong>Esophageal squamous cell carcinoma (ESCC) remains a therapeutic challenge, characterized by poor prognosis and limited treatments. Despite the established role of cancer stemness in progression and resistance, current stemness-targeting strategies, including Notch pathway inhibition, have shown suboptimal clinical efficacy. This study investigates the mechanistic role of METTL3-mediated m6A modification in ESCC stemness regulation and explores the therapeutic potential of combining METTL3 inhibitors with Notch blockade.</p><p><strong>Methods: </strong>We integrated multi-omics sequencing with functional validation. The METTL3/JAG2/Notch axis was systematically investigated using in vitro assays and in vivo xenograft models. Molecular mechanisms were elucidated through m6A-RNA immunoprecipitation, RNA stability assays, and exosome characterization.</p><p><strong>Results: </strong>METTL3 was significantly upregulated in ESCC and correlated with poor patient outcomes. Functionally, METTL3 enhanced ESCC cell proliferation, migration, and stemness maintenance through m6A-dependent regulation. Mechanistically, METTL3 catalyzed m6A modification on JAG2 mRNA, which was recognized and stabilized by IGF2BP2, leading to Notch pathway activation and upregulation of stemness markers (SOX9 and CD44). JAG2 mediated intercellular communication via both direct cell-cell contact and exosome-mediated signaling, promoting angiogenesis. Genetic ablation of JAG2 suppressed METTL3-driven tumor progression in vitro and in vivo. Importantly, pharmacological inhibition of METTL3 exhibited synergy with Notch blockade, significantly enhancing anti-tumor efficacy in preclinical models.</p><p><strong>Conclusions: </strong>Our findings establish the METTL3/JAG2 axis as a critical regulator of ESCC progression through IGF2BP2-dependent m6A modification and Notch signaling activation. The demonstrated synergy between METTL3 inhibition and Notch pathway blockade provides a novel therapeutic strategy for ESCC treatment, addressing the unmet need for effective stemness-targeting therapies.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1251-1268"},"PeriodicalIF":5.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148217927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemotherapy-induced cell cycle arrest is associated with increased claudin-18 isoform 2 expression and enhanced zolbetuximab-mediated cytotoxicity in gastric cancer.","authors":"Chiaki Takiguchi, Shotaro Nakajima, Hajime Matsuida, Hiroyuki Hanayama, Akira Matsuishi, Katsuharu Saito, Sohei Hayashishita, Dai Mitsui, Ayumi Fujii, Daiki Yamaguchi, Motonobu Saito, Hirokazu Okayama, Kosaku Mimura, Hiroshi Nakano, Tomohiro Kikuchi, Zenichiro Saze, Tomoyuki Momma, Rei Sekine, Koji Kono","doi":"10.1007/s00535-026-02443-z","DOIUrl":"10.1007/s00535-026-02443-z","url":null,"abstract":"<p><strong>Background: </strong>Claudin-18 isoform 2 (CLDN18.2) is a tight junction protein expressed in gastric mucosa and gastric cancer (GC) cells. Although chemotherapeutic agents are suggested to increase CLDN18.2 expression in GC cells, their impact on GC tissues and their underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>We examined the effects of chemotherapy on CLDN18.2 expression in human GC tissues and cell lines, and investigated the role of cell-cycle regulation in this process.</p><p><strong>Results: </strong>We found that CLDN18.2 expression was upregulated in GC tissues after chemotherapy. In GC cell lines (SNU-601, NUGC4, GSU), chemotherapeutic agents, including 5-fluorouracil, irinotecan, paclitaxel, and cisplatin, increased CLDN18.2 expression at the transcriptional level, although the response patterns varied among cell lines and agents. Since cell-cycle regulation appeared to be involved, we tested cyclin-dependent kinase (CDK) inhibitors and found that CDK1- and CDK4/6-specific inhibitors similarly enhanced CLDN18.2 expression. Importantly, both chemotherapeutic agents and CDK inhibitors significantly increased zolbetuximab-mediated antibody-dependent cellular cytotoxicity in GC cells.</p><p><strong>Conclusion: </strong>These results suggest that chemotherapeutic agents upregulate CLDN18.2 in GC cells at least in part through cell cycle arrest, and support combining zolbetuximab with chemotherapy and/or CDK inhibitors for GC treatment.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1269-1283"},"PeriodicalIF":5.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147941546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence and incidence of chronic kidney disease in patients with primary biliary cholangitis.","authors":"Jose Manuel Sousa, Sergio Rodríguez-Tajes, Manuel Hernández-Guerra, Marta Casado, Marina Berenguer, Ylenia Pérez-Castaño, Rosa Morillas, Montserrat Garcia-Retortillo, Luisa García-Buey, Miguel Ángel Simón, Elena Gómez, Francisco Jorquera, Conrado Fernández-Rodríguez, Helena Hernández-Évole, Javier Ampuero","doi":"10.1007/s00535-026-02442-0","DOIUrl":"10.1007/s00535-026-02442-0","url":null,"abstract":"<p><strong>Background: </strong>Primary biliary cholangitis (PBC) is a liver disease frequently associated with extrahepatic manifestations. Although a relationship with kidney dysfunction has been reported, data about PBC and chronic kidney disease (CKD) are limited. We assessed the prevalence and incidence of CKD and identify associated risk factors in patients with PBC.</p><p><strong>Methods: </strong>This was a multicenter retrospective study involving 1058 consecutive PBC patients. The presence of metabolic comorbidities, including diabetes, hypertension, and dyslipidemia was collected. CKD was defined as eGFR < 60 mL/min/1.73 m².</p><p><strong>Results: </strong>Baseline CKD was found in 10% of patients. The number of metabolic factors was associated with progressively lower eGFR levels and higher rates of CKD. Hypertension[OR 2.77 (95%CI 1.60-4.82)], diabetes[OR 2.17(95%CI 1.13-4.18)], ALT[OR 0.92(95%CI 0.88-0.96)], albumin[OR 0.24(95%CI 0.13-0.43)], and platelets[OR 0.996(95%CI 0.992-0.999)] were associated with baseline CKD. CKD was associated with higher mortality (32.1% vs. 7.3%). Seven percent of patients developed CKD. Baseline FIB-4 was associated with CKD incidence: < 1.45: 3% (13/428), 1.45-3.25: 10.2% (31/303), > 3.25: 13.4% (11/82). Baseline eGFR values [OR 0.93(95%CI 0.90-0.96)], cirrhosis [OR 2.31(95%CI 1.09-4.88)], hypertension [OR 2.36 (95%CI 1.14-4.88)], and albumin [OR 0.31(95%CI 0.14-0.72)] were associated with CKD occurrence. Baseline eGFR values [OR 0.90 (95%CI 0.88-0.93)], hypertension at baseline [OR 2.01(95%CI 1.06-3.81)] and progression to cirrhosis [OR 4.50(95%CI 1.96-10.30)] were related to CKD incidence in non-cirrhotic patients. In the absence of comorbidities, maintaining treatment response after follow-up showed 0.9% of de novo CKD (vs. 8%).</p><p><strong>Conclusions: </strong>One of every ten PBC patients showed CKD, mainly related to metabolic factors (hypertension and diabetes), and advanced liver disease (albumin and platelets), increasing the risk of mortality. These conditions were also related to the CKD occurrence, even in non-cirrhotic patients.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":"1312-1321"},"PeriodicalIF":5.7,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of upadacitinib for Crohn's disease in patients in East Asia: a post hoc analysis of randomized phase 3 studies.","authors":"Minhu Chen, Xiang Gao, Kenji Watanabe, Toshimitsu Fujii, Jae Hee Cheon, Shu-Chen Wei, Yuh-Ying Yeh, Yasuko Ishikawa, Patrick M Hecht, Andrew Garrison, Irina Fish, Fernando Aponte, Silvio Danese, Hiroshi Nakase","doi":"10.1007/s00535-026-02509-y","DOIUrl":"https://doi.org/10.1007/s00535-026-02509-y","url":null,"abstract":"<p><strong>Background: </strong>Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of moderate-to-severe Crohn's disease (CD). This post hoc analysis reports the efficacy and safety of upadacitinib for CD in patients in East Asia enrolled in the phase 3 clinical trials.</p><p><strong>Methods: </strong>In two induction studies (U-EXCEL [NCT03345849], U-EXCEED [NCT03345836]), adults with moderately to severely active CD were randomized 2:1 to once-daily upadacitinib 45 mg or placebo for 12 weeks. In the 52-week U-ENDURE maintenance study (NCT03345823), patients with clinical response to upadacitinib induction therapy were rerandomized 1:1:1 to once-daily upadacitinib 15 mg, upadacitinib 30 mg, or placebo. Data from patients in East Asia were evaluated.</p><p><strong>Results: </strong>In the induction studies, achievement of clinical and endoscopic outcomes occurred at higher rates with upadacitinib vs placebo at week 12 among the 204 patients in East Asia. Clinical remission per CD Activity Index (CDAI) and endoscopic response were achieved by 50.7% vs 20.6% and 61.8% vs 10.3% of patients in the upadacitinib 45-mg vs placebo groups, respectively. Similar trends for upadacitinib vs placebo were observed for the 117 patients in the maintenance study. Clinical remission per CDAI and endoscopic response were achieved by 41.5%, 54.8%, 8.8%, and 28.6%, 45.2%, 5.9% of patients receiving upadacitinib 15 mg, upadacitinib 30 mg, and placebo, respectively. The safety profile of upadacitinib was consistent with the global phase 3 population.</p><p><strong>Conclusions: </strong>Upadacitinib was efficacious in treating moderately to severely active CD among patients in East Asia and demonstrated a favorable benefit-risk profile.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide in Japanese participants with metabolic dysfunction-associated steatohepatitis: a subgroup analysis of the ESSENCE trial.","authors":"Atsushi Nakajima, Takeshi Okanoue, Yoichi Hiasa, Hirokazu Takahashi, Kwabena Opuni, Nobuyoshi Kosaka, Tomoyuki Nishida, Arun J Sanyal","doi":"10.1007/s00535-026-02507-0","DOIUrl":"https://doi.org/10.1007/s00535-026-02507-0","url":null,"abstract":"<p><strong>Background: </strong>This subgroup analysis assessed the efficacy and safety of semaglutide in the Japanese subgroup versus the overall trial population of ESSENCE (part 1) and evaluated the impact of baseline characteristics.</p><p><strong>Methods: </strong>ESSENCE is an ongoing, phase 3, multicenter, randomized, double-blind, placebo-controlled trial that includes 1197 participants with biopsy-defined metabolic dysfunction-associated steatohepatitis and liver fibrosis stage 2 or 3 randomized 2:1 to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo for 240 weeks (NCT04822181). The results of an interim analysis for efficacy conducted at week 72 involving the first 800 randomized participants are reported here (part 1).</p><p><strong>Results: </strong>One hundred and sixteen of the first 800 randomized participants included in the interim analysis for efficacy were Japanese and received semaglutide (n = 78) or placebo (n = 38). Compared with the overall population, Japanese participants were older and had a lower body mass index. Resolution of steatohepatitis and no worsening of liver fibrosis was achieved by 63.1 and 36.8% of Japanese participants receiving semaglutide and placebo, respectively (estimated difference in responder proportions [EDP]: 26.65 [95% confidence interval (CI): 7.43-45.86]). Improvement in liver fibrosis and no worsening of steatohepatitis was achieved by 36.5 and 28.9% of Japanese participants receiving semaglutide and placebo, respectively (EDP: 7.07 [95% CI: -11.48-25.62]). Based on the adverse event profiles of all participants receiving treatment, semaglutide was well tolerated in the Japanese population. Age and body mass index distribution did not meaningfully affect efficacy and safety.</p><p><strong>Conclusions: </strong>The efficacy and safety of semaglutide were directionally consistent in the Japanese population compared with those of the overall ESSENCE population.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT04822181.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148850969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucin phenotype stratifies histological malignancy in superficial non-ampullary duodenal epithelial tumors: a prospective study.","authors":"Atsushi Nakayama, Kurato Miyazaki, Kentaro Iwata, Yoko Kubosawa, Teppei Masunaga, Yukie Hayashi, Mari Mizutani, Yoshiyuki Kiguchi, Koshiro Tsutsumi, Teppei Akimoto, Yusaku Takatori, Noriko Matsuura, Makoto Mutaguchi, Tomohisa Sujino, Kaoru Takabayashi, Yasutoshi Ochiai, Tadateru Maehata, Akiko Matsubara, Ryoji Kushima, Naohisa Yahagi, Motohiko Kato","doi":"10.1007/s00535-026-02508-z","DOIUrl":"https://doi.org/10.1007/s00535-026-02508-z","url":null,"abstract":"<p><strong>Background: </strong>Superficial non-ampullary duodenal epithelial tumors (SNADETs) are being increasingly detected during routine endoscopy. However, biological malignancy and optimal risk stratification remain poorly defined. We aimed to clarify the association between mucin phenotypes and histological malignancies in SNADETs using a prospective study design.</p><p><strong>Methods: </strong>In this prospective observational study, patients with suspected SNADETs underwent a standardized magnified endoscopic examination with image-enhanced endoscopy (IEE-ME), followed by endoscopic resection. All specimens were centrally reviewed by expert gastrointestinal pathologists. Mucin phenotypes were classified as G type (gastric, predominantly gastric, or mixed) or I type (intestinal or predominantly intestinal). Histological malignancy was assessed using the Vienna classification (VCL). Clinicopathological and endoscopic factors associated with mucin phenotype and malignancy were systematically analyzed.</p><p><strong>Results: </strong>Among the 401 SNADETs, adenomas were predominant (72.1%), whereas submucosal invasive cancers were rare (2.5%). G-type SNADETs comprised 15.5% of lesions but demonstrated a markedly higher frequency beyond VCL category 4.1 compared to I-type SNADETs (P < 0.0001). The risk of histological malignancy increased stepwise with the proportion of gastric phenotypic components. Most invasive submucosal cancers exhibit a gastric phenotype. Multivariate analysis of the endoscopic findings identified a closed-loop structure, the absence of a white opaque substance on IEE-ME, and protruding morphology as independent predictors of G-type SNADETs.</p><p><strong>Conclusion: </strong>The gastric phenotype is strongly associated with increased histological malignancy in SNADETs. Specific endoscopic features can predict G-type SNADETs, suggesting that mucin phenotype-oriented endoscopic diagnosis may provide useful information for pretreatment risk stratification and treatment planning.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term impact of acute pancreatitis on patients' quality of life: a multi-center prospective study in Japan.","authors":"Masayuki Ueno, Yoshihisa Tsuji, Takaaki Eguchi, Akihisa Fukuda, Yusuke Kurita, Yukiko Takayama, Yugo Sawai, Takashi Tamura, Mamoru Takenaka, Tetsuhiro Atono, Hidenori Tanaka, Atsushi Masamune, Satoshi Yamamoto, Keisuke Ishigami, Toshihiro Kusaka, Hiroki Kawashima, Nobuhiko Hayashi, Ayako Hata, Etsuji Ishida, Hironobu Tokumasu, Norimitsu Uza, Hiroshi Seno, Hiroki Yamaue, Sohei Satoi, Yoshifumi Takeyama, Kazuichi Okazaki, Motowo Mizuno","doi":"10.1007/s00535-026-02496-0","DOIUrl":"https://doi.org/10.1007/s00535-026-02496-0","url":null,"abstract":"<p><strong>Background: </strong>Although acute pancreatitis often resolves, its long-term impact on health-related quality of life (HRQoL) and social participation remains unclear. This study investigated the longitudinal changes in HRQoL and factors affecting incomplete recovery of social participation following acute pancreatitis.</p><p><strong>Methods: </strong>This multi-center, prospective cohort study included patients aged ≥ 18 years who were hospitalized with acute pancreatitis at 20 hospitals across Japan between April 2018 and March 2024. Patients were consecutively enrolled, and health-related quality of life (HRQoL) was assessed at baseline, 3 months, and 12 months. We evaluated the severity of acute pancreatitis, demographic factors, and HRQoL parameters, including the physical component score (PCS) from the 12-item Short-Form Health Survey version 2 and self-rated health (SRH), as well as social participation status.</p><p><strong>Results: </strong>Among 284 enrolled patients, 226 were included in the primary endpoint analysis. At 3 months, 49 patients (21.7%) had incomplete recovery of social participation. Among them, 73.5% had a PCS score of less than 45, when compared with 24.9% among those with complete recovery of social participation (p < 0.01). Logistic regression analyses indicated that female sex, higher acute physiologic assessment and chronic health evaluation II score on admission, and worsened SRH were associated with incomplete recovery of social participation at 3 months. At 12 months, incomplete recovery of social participation occurred in 17.5% of patients, which was associated with younger age and worsened mental health.</p><p><strong>Conclusion: </strong>These findings support the need for phase-specific strategies: early intervention focused on physical recovery and later support targeting psychosocial recovery and social participation.</p><p><strong>Clinical trials registration: </strong>UMIN000033041.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal evolution from primary to locally recurrent rectal cancer reveals recurrence-acquired potentially actionable alterations in treatment-naïve tumors.","authors":"Mamoru Uemura, Yuta Kobayashi, Hisataka Ogawa, Yurika Nakamura, Masakatsu Paku, Nobuo Takiguchi, Chikako Kusunoki, Yuki Sekido, Mitsunobu Takeda, Tsuyoshi Hata, Atsushi Hamabe, Takayuki Ogino, Norikatsu Miyoshi, Yoshinori Kagawa, Mitsuyoshi Tei, Yuichiro Doki, Hidetoshi Eguchi","doi":"10.1007/s00535-026-02479-1","DOIUrl":"https://doi.org/10.1007/s00535-026-02479-1","url":null,"abstract":"<p><strong>Background: </strong>Locally recurrent rectal cancer (LRRC) occurs in 6-10% of patients after curative surgery. It is often regarded as a simple residual disease, yet accumulating evidence suggests that LRRC is biologically distinct from primary tumors. Clonal evolution in matched primary-recurrence pairs not exposed to preoperative therapy has not been systematically investigated.</p><p><strong>Methods: </strong>We analyzed formalin-fixed paraffin-embedded tumor specimens from 15 matched pairs of primary and locally recurrent rectal cancers not exposed to preoperative therapy using targeted next-generation sequencing of 22 colorectal cancer-related genes, including TP53, KRAS, PIK3CA, MET, and FGFR family members. Tumor areas were selectively collected to ensure high tumor purity. Mutations were classified as shared or unique, and variant allele frequencies (VAFs) and clonality (VAF > 30%) were evaluated.</p><p><strong>Results: </strong>Among 415 pathogenic mutations, 12/15 pairs (80%) harbored shared driver alterations, with TP53 shared in 11 (73%). Shared mutations showed higher VAFs in recurrences than in primaries (median 57.1% vs 47.6%; p = 0.003). Unique mutations were modestly higher in recurrences (median 5.4% vs 4.8%; p = 0.048). Clonal mutations exhibited greater VAFs at recurrence (median 86.4% vs 49.8%; p = 0.048), while the numbers of clonal mutations were comparable (32 vs 32). Potentially actionable alterations involving MET and FGFR family genes were observed in recurrent lesions in a subset of cases, including some detected at clonal levels.</p><p><strong>Conclusions: </strong>LRRC is not merely residual disease but an evolutionarily progressed tumor entity characterized by persistence and dominance of truncal drivers with acquisition of clinically relevant alterations. Profiling recurrent lesions may guide therapy as primary tumor profiling alone may miss potentially actionable alterations present in recurrent lesions.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DH-AUTAC induces ferroptosis in colorectal cancer by targeting DHODH for autophagic degradation through KCTD10-SQSTM1 signaling.","authors":"Weibing Wang, Xigang Hu","doi":"10.1007/s00535-026-02492-4","DOIUrl":"https://doi.org/10.1007/s00535-026-02492-4","url":null,"abstract":"<p><strong>Background: </strong>Dihydroorotate dehydrogenase (DHODH) is a critical enzyme involved in pyrimidine biosynthesis anda key suppressor of ferroptosis. This enzyme is commonly overexpressed in colorectal cancer (CRC), and itsupregulation facilitates the malignant progression of CRC tumors.</p><p><strong>Methods & mechanisms: </strong>This study explored the endogenous degradation mechanism of DHODH in CRC.Mechanistically, DHODH is eliminated through KCTD10-mediated selective autophagy. As a substrate-specifi cadaptor for the CUL3-RBX1 E3 ubiquitin ligase complex, KCTD10 induces K63-linked ubiquitination of DHODH. Theautophagy receptor SQSTM1/p62 subsequently recognizes the ubiquitinated DHODH and mediates its lysosomal-dependent degradation. Based on this molecular regulatory axis, we constructed DH-AUTAC, a novel autophagy-targeting chimera designed to specifi cally recruit endogenous DHODH to the autophagy system for targeteddegradation.</p><p><strong>Results: </strong>In vitro cell experiments and in vivo animal model assays consistently verifi ed the functional effi cacy ofDH-AUTAC. DH-AUTAC treatment effi ciently degraded DHODH protein, triggered robust ferroptosis, and therebymarkedly suppressed the proliferation of CRC cells and the growth of subcutaneous tumors. Pharmacologicalintervention experiments further showed that inhibiting ferroptosis completely abrogated the antitumor eff ects ofDH-AUTAC, whereas combined treatment with the autophagy and ferroptosis activator ATA194 signifi cantlyaugmented its therapeutic effi cacy. Moreover, animal model observations confi rmed that DH-AUTAC possessed agood in vivo safety profi le with no obvious adverse eff ects.</p><p><strong>Conclusion: </strong>This study identifi es a previously unreported molecular regulatory axis governing DHODH degradationin CRC. It also establishes an innovative AUTAC-based targeted protein degradation strategy to selectively activateferroptosis. Collectively, these fi ndings highlight the promising translational potential of targeted ferroptosisinduction as a novel therapeutic approach for clinical CRC treatment.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}