The Journal of Clinical Investigation最新文献

{"title":"Pulmonary fibroblast-derived stem cell factor promotes neutrophilic asthma by augmenting IL-17A production from ILC3s.","authors":"Jheng-Syuan Shao,Alan C Lai,Wei-Chang Huang,Ko-Chien Wu,Po-Yu Chi,Yao-Ming Chang,Ya-Jen Chang","doi":"10.1172/jci187372","DOIUrl":"https://doi.org/10.1172/jci187372","url":null,"abstract":"Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652503","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}

{"title":"Endocochlear potential contributes to hair cell death in TMPRSS3 hearing loss.","authors":"A Eliot Shearer,Yuan-Siao Chen,Stephanie L Rouse,Xiaohan Wang,Janmaris Marin Fermin,Kevin Ta Booth,Jasmine Moawad,Nicole Bianca Libiran,Jinan Li,Hae-Young Kim,Michael Hoa,Rafal Olszewski,Jing-Yu Lei,Ernesto Cabrera,Douglas J Totten,Bo Zhao,Jeffrey R Holt,Rick F Nelson","doi":"10.1172/jci186395","DOIUrl":"https://doi.org/10.1172/jci186395","url":null,"abstract":"Pathogenic variants in the gene TMPRSS3 are a common cause of hearing loss in humans, although the causal mechanisms remain unknown. Previous work has shown that Tmprss3Y260X/Y260X mice exhibit normal hair cell development, mechanosensory transduction, and spiral ganglion patterning, but experience rapid hair cell death from P12 to P14 at the onset of hearing. Here, we demonstrate that Tmprss3Y260X/Y260X mice display an early and temporary spike in endocochlear potential (EP) prior to the onset of hair cell death. In vitro experiments with cochlear explants from Tmprss3Y260X/Y260X mice and in vivo studies with Tmprss3Y260X/Y260X mice crossed with two different mutant models that lacked EP generation promoted hair cell survival. Furthermore, systemic administration of furosemide, a drug that reduces EP in vivo, reduced hair cell death in Tmprss3Y260X/Y260X mice. These findings suggest that extracellular factors, including EP, play a role in TMPRSS3-related hair cell survival and hearing loss, and suggest that modulating EP could be a therapeutic strategy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652504","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}

{"title":"Chemokine gradients spare graft endothelium from CD8+ T cell-mediated injury during allograft rejection.","authors":"Scott M Krummey,Jonathan S Bromberg","doi":"10.1172/jci193454","DOIUrl":"https://doi.org/10.1172/jci193454","url":null,"abstract":"T cell-mediated rejection (TCMR) develops after alloantigen-primed T cells migrate into an allograft to cause tissue damage. In contrast to antibody-mediated rejection, which creates lesions in the graft vasculature, injury to the graft vasculature is often limited during TCMR. In this issue of the JCI, Barba et al. investigated the mechanism by which the endothelium is spared from harm caused by graft-infiltrating CD8+ T cells. Endothelial cell protection was due to cell-extrinsic chemokine variations in the environment, rather than cell-intrinsic differences between endothelial and interstitial cells. The CXCL12 gradient in particular facilitated CD8+ T cell movement through the endothelial layer into the graft parenchyma. These findings suggest that targeting the CXCL12 pathway may prevent or alleviate TCMR.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629985","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}

{"title":"Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models.","authors":"Aditya K Singh,Matteo Bernabucci,Nolan M Dvorak,Zahra Haghighijoo,Jessica Di Re,Nana A Goode,Feni K Kadakia,Laura A Maile,Olumarotimi O Folorunso,Paul A Wadsworth,Cynthia M Tapia,Pingyuan Wang,Jigong Wang,Haiying Chen,Yu Xue,Jully Singh,Kali Hankerd,Isaac J Gamez,Makenna Kager,Vincent Truong,Patrick Walsh,Stephanie I Shiers,Nishka Kuttanna,Hanyue Liao,Margherita Marchi,Erika Salvi,Ilaria D'Amato,Daniela D'Amico,Parsa Arman,Catharina G Faber,Rayaz A Malik,Marina de Tommaso,Dan Ziegler,Krishna Rajarathnam,Thomas A Green,Peter M Grace,Matthew R Sapio,Michael J Iadarola,Gregory D Cuny,Diana S Chow,Giuseppe Lauria Pinter,Steve Davidson,Dustin P Green,Jun-Ho La,Jin Mo Chung,Jia Zhou,Theodore J Price,Elizabeth Salisbury,Subo Yuan,Fernanda Laezza","doi":"10.1172/jci183749","DOIUrl":"https://doi.org/10.1172/jci183749","url":null,"abstract":"Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 ligand that stabilizes FGF13/Nav1.7 CTD assembly, sensitized Na+ currents in hIPSC-derived sensory neurons and exerted pronociceptive behavioral responses in mice. ZL192's effects were abrogated by FGF13 silencing in culture and in vivo and recapitulated by FGF13 overexpression. In a model of T2DN, PW164 injection reduced mechanical hyperalgesia locally and contralaterally without systemic side effects. In donor-derived dorsal root ganglia neurons, FGF13 and Nav1.7 proteins colocalized, and the FGF13/Nav1.7 protein ratio was upregulated in patients with T2DN. Lastly, we found that SCN9A variant V1831F, associated with painless diabetic neuropathy, abolished PW164-directed modulation of the FGF13/Nav1.7 PPI interface. Thus, FGF13 is a rheostat of nociception and promising therapeutic target for diabetic neuropathy pain.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630037","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}

{"title":"Pancreatic ductal adenocarcinoma: the Everest of cancer biology.","authors":"Minh T Than,Ben Z Stanger","doi":"10.1172/jci191936","DOIUrl":"https://doi.org/10.1172/jci191936","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629976","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}

{"title":"Efficacy and safety of a therapeutic humanized FSH-blocking antibody in obesity and Alzheimer's disease models.","authors":"Anusha R Pallapati,Funda Korkmaz,Satish Rojekar,Steven Sims,Anurag Misra,Judit Gimenez-Roig,Aishwarya Gangadhar,Victoria Laurencin,Anissa Gumerova,Uliana Cheliadinova,Farhath Sultana,Darya Vasilyeva,Liam Cullen,Jonathan Schuermann,Jazz Munitz,Hasni Kannangara,Surabhi Parte,Georgii Pevnev,Guzel Burganova,Zehra Tumoglu,Ronit Witztum,Soleil Wizman,Natan Kramskiy,Liah Igel,Fazilet Sen,Anna Ranzenigo,Anne Macdonald,Susan Hutchison,Abraham Jp Teunissen,Heather Burkart,Mansi Saxena,Yelena Ginzburg,Ki Goosens,Weibin Zhou,Vitaly Ryu,Ofer Moldavski,Orly Barak,Michael Pazianas,John Caminis,Shalender Bhasin,Richard Fitzgerald,Se-Min Kim,Matthew Quinn,Shozeb Haider,Susan Appt,Tal Frolinger,Clifford J Rosen,Daria Lizneva,Yogesh K Gupta,Tony Yuen,Mone Zaidi","doi":"10.1172/jci182702","DOIUrl":"https://doi.org/10.1172/jci182702","url":null,"abstract":"There is growing evidence for direct actions of follicle-stimulating hormone (FSH) on tissues other than the ovaries and testes. Blocking FSH action, either genetically or pharmacologically, protects against bone loss, fat gain, and memory loss in mice. We thus developed a humanized FSH-blocking antibody--MS-Hu6--as a lead therapeutic for three diseases of public health magnitude--osteoporosis, obesity and Alzheimer's disease (AD) that track together in post-menopausal women. Here, we report the crystal structure of MS-Hu6 and its interaction with FSH in atomistic detail. Using our Good-Laboratory-Practice-Compliant platform (21CFR58), we formulated MS-Hu6 and the murine equivalent Hf2 at an ultra-high concentration; both formulated antibodies displayed enhanced thermal and colloidal stability. A single injection of 89Zr-labelled MS-Hu6 revealed a beta-phase t½ of 89 and 131 hours for female and male mice, respectively, with retention in regions of interest. Female mice injected subcutaneously with Hf2 displayed a dose-dependent reduction in body weight and body fat. Hf2 also rescued recognition memory and spatial learning loss in a context- and time-dependent manner in AD-prone 3xTg and APP/PS1 mice. MS-Hu6 injected into African green monkeys (8 mg/kg) intravenously, and then subcutaneously at monthly intervals, was safe, and without effects on vitals, blood chemistries or blood counts. There was a notable ~4% weight loss in all four monkeys after the first injection, which continued in two of four monkeys. We thus provide IND-enabling data towards an upcoming first-in-human study.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144639845","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}

{"title":"School-based health centers and inspiring the next generation of biomedical leaders.","authors":"Connie Cai","doi":"10.1172/jci196867","DOIUrl":"https://doi.org/10.1172/jci196867","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629966","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}

{"title":"Cancer-associated SPOP mutations enlarge nuclear size and facilitate nuclear envelope rupture upon farnesyltransferase inhibitor treatment.","authors":"Zixi Wang,Lei Li,Qi Ye,Yuzeshi Lei,Mingming Lu,Leihong Ye,Jialu Kang,Wenyue Huang,Shan Xu,Ke Wang,Jing Liu,Yang Gao,Chenji Wang,Jian Ma,Lei Li","doi":"10.1172/jci189048","DOIUrl":"https://doi.org/10.1172/jci189048","url":null,"abstract":"Nuclear size is crucial for cellular functions and often increases with malignancy. Irregular nuclei are linked to aggressive tumors, driven by genetic and epigenetic changes. However, the precise mechanisms controlling nuclear size are still not fully understood. In this study, we demonstrated that cancer-associated speckle-type POZ protein (SPOP) mutations enlarged nuclear size by reducing the protein level of lamin B2 (LMNB2), a key nuclear integrity protein. Mechanistically, SPOP bound to LMNB2 and promoted its mono-ubiquitination at lysine-484, which protected it from degradation by the E3 ubiquitin ligase WD repeat domain 26. SPOP mutations disrupted this process, leading to reduced LMNB2 levels and impaired nuclear envelope (NE) integrity. This compromised NE was more vulnerable to damage from farnesyltransferase inhibitors (FTIs), causing nuclear rupture in SPOP-mutant tumor cells. This study identified SPOP as a positive regulator of nuclear size; the findings suggest tumors with SPOP mutations may be vulnerable to FTI-based therapies.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144630036","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}

{"title":"First-generation and preclinical evaluation of an EphA5-targeted antibody-drug conjugate in solid tumors.","authors":"Fernanda I Staquicini,Fenny Hf Tang,Vanessa de Oliveira,Sun-Young Kim,Ethan R Chen,Christopher Markosian,Daniela I Staquicini,Yongjian Wu,J Kellogg Parsons,Kirstin F Barnhart,Stephen C Alley,Isan Chen,Wadih Arap,Renata Pasqualini","doi":"10.1172/jci188492","DOIUrl":"https://doi.org/10.1172/jci188492","url":null,"abstract":"Contemporary cancer treatment strategies are shifting toward targeted therapies to improve efficacy and minimize toxicity. Here, we report the design and preclinical evaluation of MBRC-101, a first-in-class antibody-drug conjugate (ADC) targeting EphA5, a receptor tyrosine kinase with an established role in embryonic development but not extensively studied in cancer. We show that EphA5 is expressed in multiple solid tumors, including cancers of the aerodigestive (non-small cell lung, head and neck, gastric, colon, and pancreatic) and genitourinary (bladder and ovary) tracts, as well as most breast cancer subsets (including triple-negative tumors), with limited expression in normal tissues. MBRC-101 is a humanized anti-EphA5 antibody conjugated to monomethyl auristatin E (MMAE) through a ThioBridge, thereby ensuring stable drug-to-antibody ratio and reducing off-target effects. MBRC-101 showed potent antitumor activity, achieving complete tumor regression in several patient-derived xenograft models. Preclinical Good Laboratory Practice-compliant toxicology studies in rats and nonhuman primates demonstrated that MBRC-101 is well tolerated, with observed toxicities limited to known MMAE off-target effects. These findings establish EphA5 as a therapeutic target in cancer and support the translational development of MBRC-101 as a promising ADC candidate for clinical evaluation, currently in a first-in-human multicenter investigational trial for patients with advanced solid tumors (ClinicalTrials.gov, NCT06014658).","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629975","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}

{"title":"An approach to targeting Nav1.7 for pain sensations.","authors":"Theodore R Cummins","doi":"10.1172/jci194126","DOIUrl":"https://doi.org/10.1172/jci194126","url":null,"abstract":"Pain is a serious medical condition with current treatments remaining limited by side effects. The Nav1.7 voltage-gated sodium channel is a crucial determinant of nociceptor excitability and a promising target for nonaddictive analgesics. However, development of blockers has been difficult. In this issue of the JCI, Singh, Bernabucci, and authors identify a strategy for reducing Nav1.7 currents. These findings identify fibroblast growth factor 13 (FGF13), a homologous factor distinct from typical growth factors (also known as FHF2B), which ramps up Nav1.7, nociceptor excitability, and pain. Compound PW164 was identified as a selective FGF13-Nav1.7 attenuator with analgesic activity. These findings highlight the power of targeting intrinsic modulators of Nav1.7 for pain management.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629984","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}