The Journal of Clinical Investigation最新文献_第5页

Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop. 靶向MTAP通过前馈循环增加三阴性乳腺癌中PARP抑制剂的易感性。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci188120

Xiangyu Zeng,Fei Zhao,Xinyi Tu,Yong Zhang,Wen Yang,Jing Hou,Qi Jiang,Shouhai Zhu,Zheming Wu,Yalan Hao,Lingxin Zhang,Richard M Weinshilboum,Kaixiong Tao,Liewei Wang,Zhenkun Lou

{"title":"Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop.","authors":"Xiangyu Zeng,Fei Zhao,Xinyi Tu,Yong Zhang,Wen Yang,Jing Hou,Qi Jiang,Shouhai Zhu,Zheming Wu,Yalan Hao,Lingxin Zhang,Richard M Weinshilboum,Kaixiong Tao,Liewei Wang,Zhenkun Lou","doi":"10.1172/jci188120","DOIUrl":"https://doi.org/10.1172/jci188120","url":null,"abstract":"Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to High IFN-γ and low SLPI mark severe asthma in mice and humans. 在小鼠和人类中，高IFN-γ和低SLPI标志着严重哮喘。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci195762

Mahesh Raundhal,Christina Morse,Anupriya Khare,Timothy B Oriss,Jadranka Milosevic,John Trudeau,Rachael Huff,Joseph Pilewski,Fernando Holguin,Jay Kolls,Sally Wenzel,Prabir Ray,Anuradha Ray

引用次数: 0

Endometriosis and ovulatory menstruation: beyond the Sampson principle. 子宫内膜异位症与排卵月经：超越桑普森原理。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci188787

Serdar E Bulun

{"title":"Endometriosis and ovulatory menstruation: beyond the Sampson principle.","authors":"Serdar E Bulun","doi":"10.1172/jci188787","DOIUrl":"https://doi.org/10.1172/jci188787","url":null,"abstract":"Endometriosis is an estrogen-dependent chronic inflammatory syndrome characterized by viable endometrial tissue outside the uterine cavity and associated with pain and infertility. Endometriosis, as tissue or a pathological process, is dynamic in that its establishment and progression require repeated episodes of retrograde travel of shed endometrial tissue, which implants in the lower abdominal cavity following ovulatory cycles and survives. Estrogen-rich follicular fluid released onto peritoneal surfaces during ovulation may also support endometriotic implants. DNA evidence indicates that endometriosis originates from eutopic endometrial tissue, which may reach the abdominal cavity in a retrograde manner primarily via the uterine tubes. Unlike uterine bleeding associated with non-ovulatory circumstances, retrograde menstruation following an ovulation maximizes shedding of epithelial cells localized to deep invaginations of the basalis portion of the endometrium, which likely carry somatic cancer-driver mutations such as KRAS. The attached endometrial stromal cells are mostly mutation free but display epigenetic defects including overexpression of aromatase and estrogen receptor-β and downregulation of progesterone receptor, causing estrogen excess and progesterone resistance. These tissue clones may form implants in involuting ovarian corpus luteum cysts and peritoneal surfaces and induce tissue remodeling and fibrosis, manifested as deep-infiltrating endometriosis. The first-line treatment for chronic pelvic pain associated with endometriosis is suppression of ovulation, with the goal of relieving pain. Infertility is often managed using in vitro fertilization, which improves the embryo quality and alters endometrial development.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/- mice. 单倍体功能不全修复策略可纠正Nf1+/-小鼠的神经行为缺陷。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci188932

Su Jung Park,Jodi L Lukkes,Ka-Kui Chan,Hayley P Drozd,Callie B Burgin,Shaomin Qian,Morgan McKenzie Sullivan,Cesar Gabriel Guevara,Nolen Cunningham,Stephanie Arenas,Makenna A Collins,Jacob Zucker,JinHee Won,Abbi Smith,Li Jiang,Dana K Mitchell,Steven D Rhodes,Steven P Angus,D Wade Clapp

{"title":"A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/- mice.","authors":"Su Jung Park,Jodi L Lukkes,Ka-Kui Chan,Hayley P Drozd,Callie B Burgin,Shaomin Qian,Morgan McKenzie Sullivan,Cesar Gabriel Guevara,Nolen Cunningham,Stephanie Arenas,Makenna A Collins,Jacob Zucker,JinHee Won,Abbi Smith,Li Jiang,Dana K Mitchell,Steven D Rhodes,Steven P Angus,D Wade Clapp","doi":"10.1172/jci188932","DOIUrl":"https://doi.org/10.1172/jci188932","url":null,"abstract":"Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations of the NF1 tumor suppressor gene resulting in the loss of function of neurofibromin, a GTPase-activating protein (GAP) for Ras. While the malignant manifestations of NF1 are associated with loss of heterozygosity of the residual WT allele, the nonmalignant neurodevelopmental sequelae, including autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) are prevalent morbidities that occur in the setting of neurofibromin haploinsufficiency. We reasoned that augmenting endogenous levels of WT neurofibromin could serve as a potential therapeutic strategy to correct the neurodevelopmental manifestations of NF1. Here, we used a combination of genetic screening and genetically engineered murine models to identify a role for the F-box protein FBXW11 as a regulator of neurofibromin degradation. Disruption of Fbxw11, through germline mutation or targeted genetic manipulation in the nucleus accumbens, increased neurofibromin levels, suppressed Ras-dependent ERK phosphorylation, and corrected social learning deficits and impulsive behaviors in male Nf1+/- mice. Our results demonstrate that preventing the degradation of neurofibromin is a feasible and effective approach to ameliorate the neurodevelopmental phenotypes in a haploinsufficient disease model.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Co-targeting TGF-β and PD-L1 sensitizes triple-negative breast cancer to experimental immunogenic cisplatin-eribulin chemotherapy doublet. 联合靶向TGF-β和PD-L1使三阴性乳腺癌对实验性免疫原性顺铂-艾瑞布林双重化疗增敏。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci184422

Laura Kalfeist,Fanny Ledys,Stacy Petit,Cyriane Poirrier,Samia Kada Mohammed,Loïck Galland,Valentin Derangère,Alis Ilie,David Rageot,Romain Aucagne,Pierre-Simon Bellaye,Caroline Truntzer,Marion Thibaudin,Mickaël Rialland,François Ghiringhelli,Emeric Limagne,Sylvain Ladoire

{"title":"Co-targeting TGF-β and PD-L1 sensitizes triple-negative breast cancer to experimental immunogenic cisplatin-eribulin chemotherapy doublet.","authors":"Laura Kalfeist,Fanny Ledys,Stacy Petit,Cyriane Poirrier,Samia Kada Mohammed,Loïck Galland,Valentin Derangère,Alis Ilie,David Rageot,Romain Aucagne,Pierre-Simon Bellaye,Caroline Truntzer,Marion Thibaudin,Mickaël Rialland,François Ghiringhelli,Emeric Limagne,Sylvain Ladoire","doi":"10.1172/jci184422","DOIUrl":"https://doi.org/10.1172/jci184422","url":null,"abstract":"In preclinical mouse models of triple-negative breast cancer (TNBC), we show that a combination of chemotherapy with cisplatin (CDDP) and eribulin (Eri) was additive from an immunological point of view and was accompanied by the induction of an intratumoral immune and inflammatory response favored by the immunogenic cell death induced by CDDP, as well as by the vascular and tumor stromal remodeling induced by each chemotherapy. Unexpectedly, despite the favorable immune context created by this immunomodulatory chemotherapy combination, our models remained refractory to the addition of anti-PD-L1 immunotherapy. These surprising observations led us to discover that CDDP chemotherapy was simultaneously responsible for the production of TGF-β by several populations of cells present in tumors, which favored the emergence of different subpopulations of immune cells and cancer-associated fibroblasts characterized by immunosuppressive properties. Accordingly, co-treatment with anti-TGF-β restored the immunological synergy between this immunogenic doublet of chemotherapy and anti-PD-L1 in a CD8-dependent manner. Translational studies revealed the unfavorable prognostic effect of the TGF-β pathway on the immune response in human TNBC, as well as the ability of CDDP to induce this cytokine also in human TNBC cell lines, thus highlighting the clinical relevance of targeting TGF-β in the context of human TNBC treated with chemoimmunotherapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer. 三重打击方法：蛋氨酸限制增强脑转移性三阴性乳腺癌的联合抑制剂。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci193171

Samyuktha Suresh,James M Ford

引用次数: 0

Purinergic signaling modulates CD4+ T cells with cytotoxic potential during Trypanosoma cruzi infection. 嘌呤能信号在克氏锥虫感染期间调节CD4+ T细胞的细胞毒性潜能。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci186785

Gastón Bergero,Yanina L Mazzocco,Sebastian Del Rosso,Ruining Liu,Zoé M Cejas Gallardo,Simon C Robson,Martin Rottenberg,Maria P Aoki

{"title":"Purinergic signaling modulates CD4+ T cells with cytotoxic potential during Trypanosoma cruzi infection.","authors":"Gastón Bergero,Yanina L Mazzocco,Sebastian Del Rosso,Ruining Liu,Zoé M Cejas Gallardo,Simon C Robson,Martin Rottenberg,Maria P Aoki","doi":"10.1172/jci186785","DOIUrl":"https://doi.org/10.1172/jci186785","url":null,"abstract":"Chagas disease, caused by Trypanosoma cruzi, is endemic to Latin America and is characterized by chronic inflammation of cardiac tissues due to parasite persistence. Hypoxia within infected tissues may trigger the stabilization of HIF-1 and be linked to ATP release. Extracellular ATP exhibits microbicidal effects but is scavenged by CD39 and CD73 ectonucleotidases, which ultimately generate adenosine (ADO), a potent immunosuppressor. Here, we comprehensively study the importance of HIF-1 stabilization and the CD39/CD73/ADO axis, on CD4+ T cells with the cytotoxic phenotype, in facilitating the persistence of T. cruzi. Myocardial infection induces prominent areas of hypoxia, which is concomitant with HIF-1α stabilization in T cells and linked to early expansion of CD39+CD73+CD4+ T cell infiltrating population. Functional assays further demonstrate that HIF-1 stabilization and CD73 activity are associated with impaired CD4+ T cell cytotoxic potential. RNA-Seq analysis reveals that HIF-1 and purinergic signaling pathways are overrepresented in cardiac tissues of patients with end-stage Chagas disease. The findings highlight a major effect of purinergic signaling on CD4+ T cells with potential cytotoxic capacity in the setting of T. cruzi infection and have translational implications for therapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Blocking immune checkpoint LAIR1 with antibody blockade or 3-in-1 CAR T cells enhances antitumor response. 用抗体阻断或3合1 CAR - T细胞阻断免疫检查点LAIR1增强抗肿瘤反应。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci184043

Haipeng Tao,Dongjiang Chen,Changlin Yang,Duy T Nguyen,Georges Abboud,Ruixuan Liu,Tianyi Liu,Avirup Chakraborty,Alicia Y Hou,Nicole A Petit,Muhammad Abbas,Robert W Davis,Janie Zhang,Christina Von Roemeling,Mohammed O Gbadamosi,Linchun Jin,Tongjun Gu,Tuo Lin,Pengchen Wang,Alfonso Pepe,Diego Ivan Pedro,Hector R Mendez-Gomez,Chao Xie,Aida Karachi,Frances Weidert,Dan Jin,Chenggang Wang,Kaytora Long-James,Elizabeth K Molchan,Paul Castillo,John A Ligon,Ashley P Ghiaseddin,Elias J Sayour,Maryam Rahman,Loic P Deleyrolle,Betty Ys Kim,Duane A Mitchell,W Gregory Sawyer,Jianping Huang

{"title":"Blocking immune checkpoint LAIR1 with antibody blockade or 3-in-1 CAR T cells enhances antitumor response.","authors":"Haipeng Tao,Dongjiang Chen,Changlin Yang,Duy T Nguyen,Georges Abboud,Ruixuan Liu,Tianyi Liu,Avirup Chakraborty,Alicia Y Hou,Nicole A Petit,Muhammad Abbas,Robert W Davis,Janie Zhang,Christina Von Roemeling,Mohammed O Gbadamosi,Linchun Jin,Tongjun Gu,Tuo Lin,Pengchen Wang,Alfonso Pepe,Diego Ivan Pedro,Hector R Mendez-Gomez,Chao Xie,Aida Karachi,Frances Weidert,Dan Jin,Chenggang Wang,Kaytora Long-James,Elizabeth K Molchan,Paul Castillo,John A Ligon,Ashley P Ghiaseddin,Elias J Sayour,Maryam Rahman,Loic P Deleyrolle,Betty Ys Kim,Duane A Mitchell,W Gregory Sawyer,Jianping Huang","doi":"10.1172/jci184043","DOIUrl":"https://doi.org/10.1172/jci184043","url":null,"abstract":"Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME) and dampen the immune response, negatively affecting patient survival. Therefore, targeting TAMs could address the limitations of current cancer treatments. However, drug development in this area remains limited. The Leukocyte-associated Immunoglobulin-like Receptor-1 (LAIR1), also called CD305, is prominently expressed on the surface of TAMs. We have uncovered a previously unrecognized immunosuppressive LAIR1 → Factor XIII A (FXIII-A) → Collagen IV pathway across various cancer types. Inhibition of LAIR1, either through knockout (Lair1-/-), antibody blockade (aLAIR1), or a chimeric antigen receptor (CAR) design (3-in-1 CAR by combining tumor targeting, T cell trafficking, and remodeling of the immunosuppressive TME in one CAR construct) provides enhanced antitumor response. LAIR1 inhibition enhances peripheral and intratumoral CD8 memory T-cell populations, induces a phenotypic shift of M2-like Macrophages towards M1, and normalizes tumor collagen IV and structural components in the TME, facilitating effective tumor-T cell interactions and tumor suppression. Enhanced antitumor responses were observed when Lair1-/- or aLAIR1 was used alone or combined with CAR T cells or when the 3-in-1 CAR T cells were used solely in chemotherapy-radiation-PD-1 blockade-resistant tumor models. These findings position LAIR1 inhibition as a promising strategy for cancer immunotherapies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MASLD in children: integrating epidemiological trends with mechanistic and translational advances. 儿童MASLD：将流行病学趋势与机制和转化进展相结合。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci186422

Jeffrey B Schwimmer,Sudha B Biddinger,Samar H Ibrahim

{"title":"MASLD in children: integrating epidemiological trends with mechanistic and translational advances.","authors":"Jeffrey B Schwimmer,Sudha B Biddinger,Samar H Ibrahim","doi":"10.1172/jci186422","DOIUrl":"https://doi.org/10.1172/jci186422","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common pediatric liver disease, affecting approximately 10% of children. Its prevalence is rising at an alarming rate, with cases increasingly identified even in early childhood. While MASLD shares key features across the lifespan, its earlier onset reflects developmental vulnerabilities and unique mechanistic drivers. Perinatal influences, including maternal obesity, gestational diabetes, and early-life nutritional exposures, play a central role by disrupting metabolic programming, driving mitochondrial dysfunction, and inducing epigenetic modifications. These early stressors interact with genetic predispositions, such as PNPLA3 and TM6SF2 variants, to amplify susceptibility and shape disease severity. Pediatric MASLD also exhibits distinct histological features, particularly predominant periportal (zone 1) steatosis, inflammation, and fibrosis, which contrast with the centrilobular or pericentral (zone 3) patterns often seen in adults. These findings provide insight into spatial heterogeneity, developmental pathophysiology, and unique disease progression trajectories in children. Addressing MASLD in children requires pediatric-specific approaches to diagnosis, risk stratification, and intervention. By integrating epidemiological trends, mechanistic insights, and translational advances, this Review highlights opportunities for targeted therapies and prevention strategies aimed at mitigating early-life drivers of MASLD, reducing disease burden, and improving long-term outcomes.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144533566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hepcidin sustains Kupffer cell immune defense against bloodstream bacterial infection via gut-derived metabolites in mice. Hepcidin通过小鼠肠道代谢物维持库普弗细胞对血流细菌感染的免疫防御。

The Journal of Clinical Investigation Pub Date : 2025-07-01 DOI: 10.1172/jci189607

Yihang Pan,Lihua Shen,Zehua Wu,Xueke Wang,Xiwang Liu,Yan Zhang,Qinyu Luo,Sijin Liu,Xiangming Fang,Qiang Shu,Qixing Chen

{"title":"Hepcidin sustains Kupffer cell immune defense against bloodstream bacterial infection via gut-derived metabolites in mice.","authors":"Yihang Pan,Lihua Shen,Zehua Wu,Xueke Wang,Xiwang Liu,Yan Zhang,Qinyu Luo,Sijin Liu,Xiangming Fang,Qiang Shu,Qixing Chen","doi":"10.1172/jci189607","DOIUrl":"https://doi.org/10.1172/jci189607","url":null,"abstract":"Bloodstream bacterial infections cause one-third of deaths from bacterial infections, and eradication of circulating bacteria is essential to prevent disseminated infections. We here found that hepcidin, the master regulator of systemic iron homeostasis, affected Kupffer cell (KC) immune defense against bloodstream bacterial infections by modulating the gut commensal bacteria-derived tryptophan derivative indole-3-propionic acid (IPA). Hepcidin deficiency impaired bacterial capture by KCs and exacerbated systemic bacterial dissemination through morphological changes in KCs. Gut microbiota depletion and fecal microbiota transplantation revealed that the gut microbiota mediated the alteration of KCs volume. Mechanistically, hepcidin deficiency led to a decreased abundance of the IPA-producing commensal Lactobacillus intestinalis and a concomitant reduction in the gut-to-liver shuttling of its metabolite IPA. IPA supplementation or Lactobacillus intestinalis colonization restored the KC volume and hepatic immune defense against bloodstream bacterial infection in hepcidin-deficient mice. Moreover, hepcidin levels in patients with bacteremia were associated with days of antibiotic usage and hospitalization. Collectively, our findings described a previously unappreciated role of hepcidin in sustaining KC-mediated hepatic defense against bloodstream bacterial infections through the gut commensal Lactobacillus intestinalis and its tryptophan derivative IPA. More importantly, restoring the crosstalk between the gut microbiota and liver through IPA-inspired therapies may offer a promising strategy for enhancing the host defense against bloodstream bacterial infections in those with low hepcidin levels and a high risk for bacterial infections.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0