Takahama M, Wolfe KS, Richey G
… +13 more, Plaster M, Czapar A, Hernandez F, Cipurko D, Ueda T, Miki Y, Nagasaki Y, Taketomi Y, Saitoh T, Kawamoto T, Dudek SM, Murakami M, Chevrier N
J Clin Invest
· 2026 May · PMID 42065235
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Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered...Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered that the secreted phospholipase PLA2G5 is induced in colon cell types during sepsis. The genetic deletion of Pla2g5 and treatment with a PLA2G5 antibody were both associated with protection from lethal sepsis. Treatment with a PLA2G5 antibody during sepsis was associated with increased splenic red pulp macrophages and improved iron homeostasis, linking PLA2G5 to red blood cell homeostasis during sepsis. Mechanistically, bloodborne PLA2G5 led to intravascular hemolysis through its lipolytic activity on red blood cell membranes. In humans with sepsis due to bacterial, fungal, or viral infections, the serum level of PLA2G5 was elevated and predictive of disease severity and mortality. We conclude that sepsis corrupts PLA2G5 into becoming an intravascular hemolytic factor which is toxic for host red blood cells.
Zhao H, Wang P, Jiao Y
… +22 more, Huang H, Yu M, He Q, Pan C, Guo S, Huang W, Jia Y, Kong Q, Peng H, Han Y, Hou Y, Ren Z, Tao Y, Huang F, Jiang H, Sun S, Dong Y, Lin J, Yin C, Zhu X, Chen F, Ding Y
J Clin Invest
· 2026 Jun · PMID 42060361
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The human epidermal growth factor receptor 2 (HER2) is a major therapeutic target in cancer. While the oncogenic effects of HER2 hyperactivation are well characterized, the biological consequences of its deficiency remai...The human epidermal growth factor receptor 2 (HER2) is a major therapeutic target in cancer. While the oncogenic effects of HER2 hyperactivation are well characterized, the biological consequences of its deficiency remain poorly defined. Here, through exome sequencing analyses of a cohort of 720 families affected by isolated or syndromic orofacial clefts, we unexpectedly identified 5 distinct rare germline HER2 variants in 5 unrelated families with growth deficits, orofacial clefts, and other craniofacial, skeletal, and auditory anomalies. In Xenopus embryos, these variants failed to recapitulate the developmental effects of WT HER2. In cultured cells, they disrupted HER2 protein stability, membrane localization, or site-specific phosphorylation, resulting in diminished ERK signaling. Strikingly, knock-in mice expressing a patient-derived HER2 variant and mice maternally exposed to Tucatinib, a recently approved anti-HER2 drug, both replicated patient phenotypes: delayed growth and diverse craniofacial abnormalities, including ocular dysgenesis, short jaws, and cleft palate. Collectively, our findings define a developmental disorder that we designate GRACE syndrome (Growth Retardation and Craniofacial Malformations Caused by HER2 Deficiency), establish HER2's essential role in human growth and craniofacial morphogenesis, and reveal that HER2-targeted therapies during pregnancy can induce craniofacial defects and lifelong growth impairment in fetuses.
J Clin Invest
· 2026 Jun · PMID 42060359
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Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is c...Neuropathic pain affects over 20 million people in the United States, and painful diabetic neuropathy (PDN), a common complication of diabetes, is among its most prevalent and treatment-resistant forms. Although PDN is characterized by nociceptor dysfunction, the upstream peripheral mechanisms remain incompletely understood. While dorsal root ganglion (DRG) nociceptor hyperexcitability is a hallmark of PDN, emerging evidence suggests that nonneuronal skin cells may modulate nociceptor function. Here, we investigated whether epidermal Langerhans cells (LCs) contribute to neuropathic pain in PDN through neuroimmune signaling. Using a clinically relevant high-fat diet (HFD) mouse model, transgenic LC ablation, behavioral assays, human skin biopsies, and single-cell RNA seq of epidermis and DRG, we found that LC density increased in male diabetic mice in parallel with mechanical allodynia. In skin samples of people with PDN, LCs exhibited increased volume and dendritic complexity correlating with diabetes duration. Genetic depletion of LCs prevented mechanical allodynia and spontaneous pain-like behavior in male, but not female, HFD mice, revealing a sex-dependent contribution. Single-cell and interactome analyses identified male-specific inflammatory LC programs, including upregulation of chemokine signaling pathways. Consistently, LC secretome profiling showed increased CCL2 release, and local CCR2 blockade reversed allodynia. These findings identify epidermal LCs as peripheral regulators of PDN pain and highlight sex-dependent chemokine-mediated neuron-immune communication at the skin-nerve interface.
Jo HJ, Kim A, Rho H
… +24 more, Park AK, Kim GH, Jo SJ, Yuxin H, Hong YJ, Yeon JM, Yu HC, Song MY, Park J, Jeong YH, Hong SE, Yeon HJ, Oh DY, Scherer PE, Choi CS, Lee DH, Ki SH, Kang KW, Choi M, Park BH, Bae EJ, Kim SG, Kim W, Han CY
J Clin Invest
· 2026 Jun · PMID 42048168
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Iron overload has emerged as a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), a growing global health concern. Despite this association, the precise mechanisms by which hepa...Iron overload has emerged as a significant risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), a growing global health concern. Despite this association, the precise mechanisms by which hepatic iron and its regulatory genes connect liver pathology to systemic metabolic dysfunction remain elusive. Here, we demonstrate that humoral signals originating from iron-overloaded hepatocytes acted as critical mediators driving systemic metabolic dysfunction in MASLD. Ferroportin (FPN, SLC40A1), the sole cellular iron exporter, exhibited markedly reduced expression in hepatocytes of both patients with MASLD and mouse models of the disease, concomitant with hepatic iron accumulation. Functionally, hepatocyte-specific FPN deletion significantly exacerbated diet-induced obesity and insulin resistance, with these metabolic perturbations accompanied by decreased energy expenditure and impaired thermogenic capacity. Mechanistically, we establish that hepatic iron accumulation resulting from FPN deficiency enhanced the production of 2 specific hepatokines, fetuin-A and LECT2, through activation of the transcription factor FoxO1. Notably, therapeutic interventions - including genetic silencing of these hepatokines, hepatocyte-specific FPN overexpression, or oral iron chelation - effectively reversed the metabolic dysfunction phenotypes. These findings provide critical insights into the pathophysiological mechanisms linking MASLD to systemic metabolic disorders and highlight promising therapeutic strategies to combat these diseases.
Pecoraro F, Perico L, Casiraghi F
… +11 more, Rizzo P, Trillini M, Angeletti A, Podestà MA, Kajana X, Spennacchio A, Todeschini M, Mister M, Castellano G, Benigni A, Remuzzi G
J Clin Invest
· 2026 Jul · PMID 42048157
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BACKGROUNDAnti-nephrin autoantibodies have emerged as a putative pathogenic driver in a subset of patients with podocytopathies, including those with posttransplant disease recurrence.METHODSWe measured anti-nephrin auto...BACKGROUNDAnti-nephrin autoantibodies have emerged as a putative pathogenic driver in a subset of patients with podocytopathies, including those with posttransplant disease recurrence.METHODSWe measured anti-nephrin autoantibodies in a cohort of 65 patients with podocytopathy associated with steroid-sensitive nephrotic syndrome (n = 39) and steroid-resistant nephrotic syndrome (n = 26) and in 34 patients with posttransplant podocytopathy recurrence. Fourteen patients with membranous nephropathy and 20 healthy volunteers served as controls. ELISA and immunoprecipitation assays were performed to detect anti-nephrin IgG using 2 different recombinant human nephrin proteins. Immunofluorescence analysis was performed to assess gG deposition and its colocalization with nephrin in renal biopsies.RESULTSWhen using an ELISA based on murine cell-derived human antigen, the highest positivity was found in healthy volunteers (55%), correlating with levels of circulating natural anti-α-galactose-α-1,3-galactose antibodies. This cross-reactivity was abrogated with recombinant human nephrin expressed in human cells. In this setting, very low prevalence (<5%) of anti-nephrin antibody-positive patients was found in steroid-sensitive and -resistant nephrotic syndrome cohorts and in patients with posttransplant disease recurrence. These frequencies were comparable to healthy volunteers. Using confocal and super-resolution microscopy, only trace amounts of IgM, but no IgG, were found in the glomeruli of analyzed biopsies, which did not colocalize with nephrin.CONCLUSIONWith the methodology presented here, anti-nephrin reactivity was extremely rare and occurred at comparably low frequencies in healthy controls, native-kidney podocytopathies, and posttransplant disease recurrence. This suggests that these autoantibodies are not inherently disease specific and may not serve as a broad biomarker across podocytopathies.TRIAL REGISTRATIONClinicalTrials.gov NCT06334692.FUNDINGThe Medici di Marignano family.
Lin CC, Rose J, Mestre AA
… +20 more, Ding CC, Chen SY, Choy SM, Goh KY, Jiang W, Lee WX, Jiang Q, Chen Y, Sun T, Wu J, Chen Y, Oh Y, Jeong P, Hong J, Chua K, Fitzgerald MC, Zhang GF, Tang HW, Zhou P, Chi JT
J Clin Invest
· 2026 Jun · PMID 42033660
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CoA facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well characterized, the mechanisms governing CoA degradation remain poorly understood. Here, w...CoA facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well characterized, the mechanisms governing CoA degradation remain poorly understood. Here, we identify the Metazoan Homolog of SpoT, MESH1, as a CoA phosphatase that dephosphorylates CoA at the 3' position of the ribose ring to form dephospho-CoA. Recent studies have shown that CoA, similar to glutathione, is a cysteine-derived metabolite that protects cells against ferroptosis. Ferroptosis induced by blocking cystine import depletes CoA biosynthesis, while CoA restoration rescues cells from ferroptosis. We found that MESH1 knockdown preserved CoA levels by preventing its degradation, contributing to ferroptosis protection, indicating the bifunctional role of MESH1 in regulating CoA and previously reported NADPH. Mechanistically, MESH1 knockdown elevates CoA levels, maintaining a functional mitochondrial thioredoxin system, thereby preventing mitochondrial lipid peroxidation. In Drosophila, we found that dMesh1 overexpression leads to ferroptosis-mediated muscle atrophy, which can be rescued by increasing CoA and NADPH levels. Taken together, these findings establish MESH1 as a key phosphatase that governs ferroptosis sensitivity by coordinating CoA and NADPH homeostasis, unveiling a link between CoA degradation, mitochondrial integrity, and muscle health.
The liver plays a critical role in lipid homeostasis, where lipids are either secreted as very-low-density lipoproteins (VLDL) or stored in lipid droplets (LDs). However, the regulatory mechanisms governing these two int...The liver plays a critical role in lipid homeostasis, where lipids are either secreted as very-low-density lipoproteins (VLDL) or stored in lipid droplets (LDs). However, the regulatory mechanisms governing these two interconnected processes remain poorly understood. Here, we demonstrate that SEC16B functions as a lipid-responsive regulator in the liver, promoting VLDL secretion and LD expansion to handle lipid flux and maintain lipid homeostasis. Genome-wide association studies have identified single-nucleotide polymorphisms in SEC16B to be highly associated with serum lipid levels in humans. Hepatic Sec16b deficiency decreases serum lipid levels by impairing VLDL secretion through mechanisms that are at least partially independent of microsomal triglyceride transfer protein (MTP)-mediated ApoB lipidation and COPII-mediated intracellular trafficking. SEC16B partially localizes at ER-LD contact sites and promotes LD expansion by facilitating the targeting of ER proteins to LDs. More importantly, suppression of Sec16b dramatically lowers serum lipid levels and reduces atherosclerotic lesion size in Ldlr null mice. These data reveal a mechanism that coordinates VLDL and LD metabolism and suggest SEC16B as a potential therapeutic target for atherosclerosis treatment.
Wang H, Jiang H, He S
… +18 more, Ren S, Li H, Liu W, Zhou C, Zhu P, Chen K, Cao W, Qin Y, Du D, Xiao N, Huang H, Ko CJ, Zheng Y, Wang B, Zou Q, Shi JH, Li X, Jie Z
J Clin Invest
· 2026 Jun · PMID 42024470
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Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study...Type 1 conventional dendritic cells (cDC1s) play an integral role in mediating immune responses and maintaining homeostasis, yet the molecular mechanisms underlying their functions remain poorly understood. In this study, we identified dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as a key kinase that responded to TLR and growth factor stimulation and acted as an essential regulator of cDC1 function. Genetic ablation of Dyrk1a specifically in cDC1s impaired antitumor immunity and accelerated tumor progression in murine models. Mechanistically, DYRK1A mediated the phosphorylation of the mTOR complex 1 (mTORC1) inhibitor TSC2 at serine 540, triggering the degradation of TSC2 and promoting mTORC1 signaling in cDC1s. Notably, Tsc2 deletion in Dyrk1a-deficient cDC1s remarkably restored their antitumor immune functions. Furthermore, DYRK1A-mediated mTORC1 signaling in cDC1s positively correlated with effector T cell responses across multiple human cancers. Our findings highlight a critical role for the DYRK1A/TSC2/mTORC1 signaling pathway in regulating cDC1 functions in antitumor immunity, offering potential strategies to improve cancer immunotherapy.
Cabodevilla AG, Calistru C, Younis W
… +17 more, Nasias D, Ho TW, Anaganti N, Valmiki S, Rajan S, Gjini J, Kore R, Hannemann C, Davidson NO, Vaisar T, Kanter JE, Bornfeldt KE, Fisher EA, Lee WL, Madl T, Hussain MM, Goldberg IJ
J Clin Invest
· 2026 Jun · PMID 42024468
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Apolipoprotein B-containing (APOB-containing) lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin recepto...Apolipoprotein B-containing (APOB-containing) lipoproteins contribute to atherosclerosis by entering the arterial wall through the endothelial cell (EC) surface receptors scavenger receptor-BI (SR-BI) and activin receptor-like kinase 1 (ALK1). We used N-terminal fragments of APOB, molecular modeling, and site-directed mutagenesis to identify and block the binding of chylomicrons and LDL to these receptors in cells and mice. We discovered that different APOB regions interact with SR-BI and ALK1 expressed on ECs. APOB48 lipoproteins were only internalized by SR-BI. A fragment of APOB comprising 18% of the N-terminal sequence, APOB18, reduced the uptake and transport of both chylomicrons and LDL by ECs, whereas a shorter fragment, APOB12, only blocked ALK1-mediated uptake of APOB100-containing lipoproteins. Importantly, overexpressing APOB18 decreased atherosclerosis in hypercholesterolemic mice. These findings identify the N-terminal region of APOB as the cause of atherosclerosis and illustrate an approach to treating or preventing vascular disease.
Zhang S, Liu J, Li Y
… +9 more, Wang Y, Wang L, Xu M, Li Y, Dong G, Wang S, Li Y, Cai Z, Zhao B
J Clin Invest
· 2026 Jun · PMID 42024446
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Typ515 (W515) mutations in the protein MPL are one of the key driver mutations promoting BCR-ABL-negative myeloproliferative neoplasms (MPNs), but, to our knowledge, their effects on hematopoietic stem cells (HSCs) and M...Typ515 (W515) mutations in the protein MPL are one of the key driver mutations promoting BCR-ABL-negative myeloproliferative neoplasms (MPNs), but, to our knowledge, their effects on hematopoietic stem cells (HSCs) and MPN-related hematological abnormalities have not been studied in physiological contexts. Here, we established a MplW514L knock-in mouse model, which largely mimics human MPLW515L mutation during hematopoiesis. The mutant mice developed an essential thrombocythemia-like (ET-like) MPN phenotype, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically, we observed that the MplW514L-conditioned HSC compartment had a unique disease-initiating capacity; however, it did not exhibit a obvious advantage of competitive repopulation over the WT control. Notably, single-cell analysis and flow cytometry profiles support that MplW514L expression led to a significant expansion of megakaryocyte-biased stem cell fate within the HSC pool. Finally, JAK2 inhibitor treatment phenotypically alleviated the ET signs but failed to eliminate the disease-initiating HSCs. These findings underscore the etiology of physiological expression of the MPLW515L mutation in HSCs and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.
Majcher A, Khan R, Buder K
… +3 more, Bourquin F, Saba JD, Hornemann T
J Clin Invest
· 2026 Jun · PMID 42024444
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Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS), also known as nephrotic syndrome type 14, is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enz...Sphingosine-1-phosphate lyase (SPL) insufficiency syndrome (SPLIS), also known as nephrotic syndrome type 14, is an autosomal recessive multisystem disorder caused by loss-of-function mutations in SGPL1, encoding the enzyme responsible for the terminal degradation of sphingosine-1-phosphate (S1P). We investigated a patient carrying a previously undescribed c.1084T>A (p.Ser362Thr) SGPL1 variant and analyzed the metabolic and cellular consequences of SPL deficiency, using patient fibroblasts, SGPL1-KO HEK293T cells, and Sgpl1-/- and Sgpl1rosa+fl/fl mice. Metabolic stable isotope labeling revealed that SPL deficiency does not invariably result in S1P accumulation. Instead, SPL-deficient cells maintain near-normal S1P levels through (a) feedback regulation of de novo sphingolipid synthesis via the ORMDL-ceramide axis and (b) increased diversion of excess ceramides into glycosphingolipids. However, perturbation of sphingolipid homeostasis, either by exogenous sphingolipid load or disruption of compensatory regulation, induces pathological intracellular S1P accumulation. In vivo, Sgpl1-/- mice had pronounced urinary S1P excretion and renal S1P enrichment, accompanied by cytoskeletal disorganization and impaired epithelial morphogenesis. Mechanistically, we identify aberrant Rho/ROCK signaling as a key mediator of S1P-driven cytoskeletal dysregulation. Pharmacological ROCK inhibition with fasudil mitigated renal cytoskeletal defects in Sgpl1-/- and Sgpl1rosa+fl/fl mice and partially restored epithelial architecture. These findings redefine the metabolic consequences of SPL deficiency and identify S1P-driven Rho/ROCK hyperactivation as a tractable therapeutic target in SPLIS.
He M, Xu B, Bose PG
… +19 more, McCullough MJ, Sellers RS, Zong X, Qi W, Banten BL, Tune MK, Zimmerman MP, Mullins G, Miller BC, Milner JJ, Whitmire JK, Tsagaratou A, Shpargel KB, Doerschuk CM, Wang YD, Steele JA, Pruett-Miller SM, Feng Y, Mock JR
J Clin Invest
· 2026 Jul · PMID 42024441
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Tregs expressing forkhead box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg identity and s...Tregs expressing forkhead box P3 (FOXP3) play crucial roles in maintaining immune tolerance and tissue integrity. EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg identity and suppressive function upon activation. Here, we demonstrate that the H3K27 lysine demethylase KDM6B, which catalyzes the opposing reaction to EZH2, is also required for Treg identity and function after activation. Treg-specific deletion of Kdm6b impaired tissue Treg fate and function. KDM6B was upregulated after T cell antigen receptor signaling in Tregs and contributed to the regulation of Treg-associated gene expression through both direct and indirect mechanisms. A subset of Treg functional genes were direct targets of KDM6B and were co-occupied by FOXP3 at cis-regulatory regions, where KDM6B recruitment limited H3K27me3 accumulation. More broadly, KDM6B-dependent H3K27 demethylation facilitated Treg gene expression programs that supported tissue Treg homeostasis.
Mencacci NE, Minakaki G, Maroofian R
… +36 more, De Pace R, Paimboeuf A, Branco Fonseca T, Abramova T, Shannon P, Chitayat D, Magrinelli F, Peng WJ, Chatterjee D, Eldessouky SH, Baptista J, Marton T, Vogt J, Ortigoza-Escobar JD, Martorell L, Gómez-Chiari M, Wentzensen IM, Kamsteeg EJ, Zaki MS, Scardamaglia A, Zifarelli G, Al-Hassnan ZN, Miller E, Shinar S, Matsa LS, Appikonda SHC, Otaify GA, Al-Thihli K, Al-Maawali A, Schwake M, Severino M, Houlden H, Patten SA, Bonifacino JS, Bhatia KP, Krainc D
J Clin Invest
· 2026 Jun · PMID 42012897
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BORCS5 encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from 9 families with bi-allelic BORCS5 variants, revea...BORCS5 encodes a subunit of the BLOC-One-Related Complex (BORC), which is known to promote anterograde movement and fusion of lysosomes. We identified 16 individuals from 9 families with bi-allelic BORCS5 variants, revealing a spectrum of neurodevelopmental and neurodegenerative phenotypes. Carriers of homozygous protein-truncating variants (PTVs), resulting in complete loss of BORCS5, presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of neuroaxonal dystrophy. Individuals with missense or splice-site variants presented differently, with microcephaly, developmental epileptic encephalopathy, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination, corpus callosum abnormalities, and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 KO in zebrafish resulted in microcephaly, motor deficits, and increased seizure susceptibility, mirroring the patients' clinical presentation. At the cellular level, only BORCS5 PTVs, but not missense variants, led to perinuclear lysosomal clustering and impaired lysosomal axonal trafficking in induced pluripotent stem cell-derived forebrain neurons. However, PTVs and missense variants were associated with reduced lysosomal proteolysis and activity of lysosomal hydrolases glucocerebrosidase and cathepsin B, indicating lysosomal dysfunction. Our study reveals a role for BORCS5 in modulation of lysosomal function, in addition to its known role in lysosome movement and fusion, possibly underlying the diverse clinical manifestations in individuals with BORCS5-related disorders.
Balasubramaniam A, Pavlov D, Du Y
… +12 more, Reeves J, Harzman A, Liu Y, Cingolani F, Yuan X, Patel JM, Mwangi SM, He P, Hart CM, Hu W, Christofi FL, Srinivasan S
J Clin Invest
· 2026 Jun · PMID 42012889
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The Western diets (WD), high in saturated fats such as palmitic acid (PA), promotes enteric neurodegeneration and motility disorders. Using murine models, in vitro systems, and human myenteric ganglia, we investigated wh...The Western diets (WD), high in saturated fats such as palmitic acid (PA), promotes enteric neurodegeneration and motility disorders. Using murine models, in vitro systems, and human myenteric ganglia, we investigated whether a WD and PA drive iron-dependent ferroptotic injury in the enteric nervous system (ENS). Mice were fed a control diet (CD) or a WD for 12 weeks, with or without systemic AAV9-MaCPNS2 delivery of Nfe2l2 to enteric neurons. Colonic motility was assessed by a bead expulsion assay. We assessed ferroptosis using convergent readouts including iron dysregulation (transferrin receptor 1 [TfR1], ferritin heavy chain 1 [FTH1], labile and mitochondrial iron [Fe2+]), lipid peroxidation (C11-BODIPY and 4-hydroxynonenal [4-HNE]), glutathione peroxidase 4 (GPX4) suppression, and pharmacologic inhibition by ferrostatin 1 (Fer-1) in primary enteric neurons, murine myenteric plexuses, and human networks of myenteric ganglia (nhMPG). WD-fed mice exhibited delayed colonic transit, increased TfR1 and FTH1, and vulnerability of nNOS neurons; these changes were reversed by nuclear factor erythroid 2-related factor 2; (Nfe2l2, also known as Nrf2) overexpression. RNA-seq of PA-treated immortalized murine fetal enteric neurons (IM-FENs) revealed disrupted neurotransmitter signaling, reduced mitochondrial and antioxidant programs, and increased iron import and lipid peroxidation signatures. PA increased labile Fe2+, mitochondrial ROS, membrane depolarization, Ca2+ dysregulation, 4-HNE, and mitoferrin 2 (Mfrn2), whereas Fer-1 preserved mitochondrial integrity, viability, and ENS function. In human nhMPG, PA induced enteric neuronal iron loading and ferroptosis, supporting the translational relevance to diet-associated enteric neuropathy.
Goonewardena SN, Yao S, Jurga T
… +20 more, Zhang L, Lloyd-Jones D, Damodaran D, Thyagarajan B, Jacobs DR, Shore S, Brandt EJ, Clish C, Tanriverdi K, Freedman JE, Patel CJ, Sarzynski MA, Emmer BT, Wilkins JT, Do R, Bittner V, Shah RV, Georgakis MK, Rosenson RS, Murthy VL
J Clin Invest
· 2026 Jun · PMID 42012308
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BACKGROUNDElevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associat...BACKGROUNDElevated lipoprotein(a) [Lp(a)] is associated with a higher risk of atherosclerotic cardiovascular disease (ASCVD). Although Lp(a) is a genetically determined risk factor, the plasma proteomic features associated with Lp(a) and whether they provide information about ASCVD risk beyond Lp(a) concentration are not well characterized.OBJECTIVEWe sought to identify plasma proteomic features associated with Lp(a) concentration and to evaluate whether an Lp(a)-associated proteomic signature is associated with ASCVD phenotypes in young, healthy adults.METHODSIn the Coronary Artery Risk Development in Young Adults (CARDIA) study, we measured year 7 Lp(a) and 184 cardiovascular proteins using the Olink proximity extension assay in 3,920 participants without prior coronary heart disease. Lp(a)-associated proteomic signatures were derived using least absolute shrinkage and selection operator (LASSO) regression in a split-sample design and tested for association with coronary artery calcification (CAC), incident coronary heart disease (CHD), and high-sensitivity C-reactive protein (hs-CRP) over 27 years of follow-up. External replication was performed in the UK Biobank (n = 37,996).RESULTSLp(a) was associated with CAC (OR 1.23 [1.13-1.34]; P < 0.0001) and incident CHD (HR 1.23 [1.07-1.41]; P = 0.004). Lp(a) was correlated with proteomic features reflecting immune activation, coagulation, and vascular dysfunction. A quantitative Lp(a)-associated proteomics score was independently associated with incident CAC (standardized β = 0.40, P < 0.0001) and hs-CRP (standardized β = 0.11, P = 0.00015) after adjustment for Lp(a) concentration. In the UK Biobank, a recalibrated Lp(a)-associated proteomics score was associated with CRP, incident CHD, and all-cause mortality.CONCLUSIONSIn young adults, Lp(a) was associated with distinct proteomic features that independently predicted ASCVD phenotypes beyond Lp(a) concentration, generating hypotheses regarding biological pathways linked to Lp(a)-related cardiovascular risk.FUNDINGVA MERIT grant (1I01CX002560); Taubman Medical Research Institute (Wolfe Scholarship); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK), NIH (U01DK123013-03); National Institute on Aging (NIA), NIH (R01AG059729); National Heart, Lung and Blood Institute (NHLBI), NIH (R01HL136685); American Heart Association Strategically Focused Research Network grant in Cardiometabolic Disease (funded proteomics in CARDIA); NIH (K23MD017253 and R01HL167733); Blue Cross Blue Shield of Michigan Foundation; A. Alfred Taubman Medical Research Institute; National Institute of Nursing Research (R01NR019628); National Institute of General Medical Sciences (NIGMS), NIH (R35-GM124836). The CARDIA study was conducted and supported by the NHLBI in collaboration with the University of Alabama at Birmingham (75N92023D00002 and 75N92023D00005), Northwestern University (75N92023D00004), University of Minnesota (75N92023D00006), and the Kaiser Foundation Research Institute (75N92023D00003).ROLE OF FUNDING SOURCEThe funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Mishra R, Song S, Choradia D
… +16 more, Rudoy D, Wladyka CL, Hoang P, Kim JY, Coleman IM, Arora S, Dobersch S, Orellana AE, Lin C, Gafken PR, Corey E, Nelson PS, Kugel S, Li H, Sengupta A, Hsieh AC
J Clin Invest
· 2026 Jun · PMID 41984598
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Lineage plasticity underscores the resilience of cancer cells in the context of drug treatment. However, lineage fates can also be therapeutically directed. We demonstrate that the eukaryotic initiation factor 4E (eIF4E)...Lineage plasticity underscores the resilience of cancer cells in the context of drug treatment. However, lineage fates can also be therapeutically directed. We demonstrate that the eukaryotic initiation factor 4E (eIF4E) cap-binding domain is a critical regulator of lineage plasticity in prostate cancer. Using a first-in-class cap-binding domain inhibitor, we found that plasticity is driven by translational repression of basal keratins through a shared cis-regulatory element enciphered in their 5' untranslated regions (UTRs). Simultaneously, this stabilized the androgen receptor (AR) through translational upregulation of the deubiquitinases BAP1 and OTUD3. This lineage program is essential for cell survival and drives a druggable vulnerability. Notably, tumors resistant to AR blockade regained sensitivity upon eIF4E cap-binding domain inhibition, which reprogrammed them toward a luminal state. In patients with castration-resistant prostate cancer (CRPC), elevated eIF4E expression was associated with a basal phenotype, reduced luminal differentiation, and accelerated resistance to AR pathway inhibitors (ARPIs). These discoveries uncover a role for the eIF4E cap-binding domain in lineage plasticity and highlight that targeting this domain offers a promising strategy to overcome treatment resistance in prostate cancer.
Milanesi S, Lorenzini T, Marchetti T
… +15 more, Tintor D, Planas R, Sabet O, Malmström L, Acharya S, Williams CD, Manning ZE, Roser JH, Ehler AC, Huber M, Prader S, Vavassori S, Dutmer CM, Abbott JK, Pachlopnik Schmid J
J Clin Invest
· 2026 Jun · PMID 41984595
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CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the CD48 gene, we describe a second, unrelated patient with...CD48 is a surface molecule with immunoregulatory functions. Following our initial report of a patient with a de novo heterozygous variant at amino acid S220 in the CD48 gene, we describe a second, unrelated patient with similar features of immune dysregulation and a missense change affecting the same residue. To further elucidate the specific pathogenic mechanisms of the identified variants, we reviewed patient records, analyzed patient-derived cells, and employed complementary in vitro and in vivo model systems, including transfected cell lines and CD48-deficient mice. We demonstrate that the variants are associated with altered distribution of CD48, characterized by diminished CD48 surface expression, intracellular retention, and activation of ER stress signaling. Patient T cells displayed increased susceptibility to apoptosis, reduced antiviral responses, and enhanced inflammation. Both patients exhibited T cell lymphopenia, a restricted T cell receptor repertoire diversity, and oligoclonal expansions consistent with antigen-driven selection. In parallel, virally infected CD48-deficient mice recapitulate key aspects of the human phenotype, including delayed antiviral immune responses, impaired viral clearance, and pronounced inflammation. We conclude that identified variants compromise CD48 cell surface localization, impair T cell survival and function, and predispose to inflammation, thereby highlighting the role of CD48 in immune regulation and the prevention of excessive inflammation.
Bacos K, Perfilyev A, Karagiannopoulos A
… +24 more, Cowan E, Ofori JK, Bertonnier-Brouty L, Rönn T, Lindqvist A, Luan C, Ruhrmann S, Ngara M, Nilsson Å, Gheibi S, Lyons CL, Lagerstedt JO, Barghouth M, Esguerra JL, Volkov P, Fex M, Mulder H, Wierup N, Krus U, Artner I, Eliasson L, Prasad RB, Cataldo LR, Ling C
J Clin Invest
· 2026 Apr · PMID 41983399
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J Clin Invest
· 2026 Apr · PMID 41983398
·
Full text
Approximately 25% of individuals with type 1 diabetes (T1D) experience impaired awareness of hypoglycemia (IAH), a weakening of symptomatic neurohumoral responses to falling glucose levels that sharply increases risk of...Approximately 25% of individuals with type 1 diabetes (T1D) experience impaired awareness of hypoglycemia (IAH), a weakening of symptomatic neurohumoral responses to falling glucose levels that sharply increases risk of severe hypoglycemia. A recent study by Filip et al. used MRI-based arterial spin labeling to compare regional cerebral blood flow (CBF) responses to experimental hypoglycemia across 3 groups: individuals without T1D and individuals with T1D, with or without IAH. All groups showed a CBF response to hypoglycemia in brain regions involved in learning and interoception, among others, but the responses were qualitatively different between groups and blunted in the presence of IAH. The association between the regional CBF and the hormonal responses to hypoglycemia was inverted in IAH, compared with that in individuals with preserved awareness. The findings add to work linking changes in cognitive processing to IAH development and its persistence in some individuals.
Rampy J, Torres-Manzo AP, Hoffsmith K
… +8 more, Loberg MA, Sheng Q, Salas-Lucia F, Bianco AC, Arrojo E Drigo R, Wang H, Weiss VL, Carrasco N
J Clin Invest
· 2026 Apr · PMID 41983397
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Full text
Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (...Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) with energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt - but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for obesity therapies that tackle hypothyroidism, which are much needed, as no current obesity treatment works for everyone.