FASEB Journal[JOURNAL]
Sun
200 papers
Dissecting Immune Cell Ferroptosis via Single-Cell Multi-Omics Identifies RPL8 as a Potential Therapeutic Target for Depression.
Zhang G, He R, Du B … +7 more , Wu Y, Deng F, Zhang G, Yu J, Lin T, Sun J, Wu N
FASEB J · 2026 Jun · PMID 42249740 · Publisher ↗
Depression is a major global health burden with limited treatment efficacy. Ferroptosis, an iron-dependent form of regulated cell death, is implicated in its pathogenesis, but causal genetic links and cell-type-specific...
Depression is a major global health burden with limited treatment efficacy. Ferroptosis, an iron-dependent form of regulated cell death, is implicated in its pathogenesis, but causal genetic links and cell-type-specific mechanisms remain unclear. We employed a multi-omics framework integrating two-sample Mendelian randomization (MR) using blood cis-eQTLs (eQTLGen/GTEx) and depression (FinnGen), single-cell eQTL (sceQTL) mapping in peripheral immune cells (OneK1K cohort), bioinformatic analyses, and in silico molecular docking. MR identified 42 ferroptosis genes associated with depression. Replication across cohorts pinpointed ribosomal protein RPL8 as a key protective factor (β = -0.02 to -0.06, P < 0.05). RPL8 expression was enriched in blood/immune cells. sceQTL analysis revealed its protective effect was mediated through 11 immune cell subtypes (e.g., CD4+/CD8+ T, B, NK cells; β range: -0.016 to -0.040, P < 0.05). Molecular docking predicted high-affinity binding between RPL8 and the ferroptosis execution ligand Ncoa4-9A (ΔG = -9.3 kcal/mol). PheWAS indicated a favorable safety profile for RPL8 modulation. This study presents genetic evidence suggesting a potential causal link between ferroptosis and depression, and identifies RPL8 as a potential immune cell-mediated protective factor. Based on these findings, we propose the "immune-ribosome-ferroptosis" axis as a promising direction for future therapeutic exploration.
Association of Serum Angiopoietin-Like Protein 7 With Ferroptosis-Related Proteins in Patients With Metabolic Dysfunction-Associated Fatty Liver Disease.
Bai J, Gao Q, Liu Y … +2 more , Gao M, Zhou Y
FASEB J · 2026 Jun · PMID 42247282 · Publisher ↗
The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been increasing globally, and data indicate that ferroptosis participates in the pathogenesis of MAFLD. Angiopoietin-like protein 7 (ANGP...
The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been increasing globally, and data indicate that ferroptosis participates in the pathogenesis of MAFLD. Angiopoietin-like protein 7 (ANGPTL7) is a novel secretory glycoprotein that participates in the pathogenesis of many metabolic diseases. However, the role of ANGPTL7 in MAFLD has been poorly investigated. A total of 194 participants were enrolled, including 104 participants with MAFLD (MAFLD) and 90 healthy controls (Cons). Baseline characteristics and serum biochemical parameters were collected. Serum levels of ANGPTL7, inflammatory factors, and ferroptosis-related proteins were measured by enzyme-linked immunosorbent assay (ELISA). Liver biopsy tissues were obtained from six participants with nonalcoholic steatohepatitis and the trimmed liver tissues from five healthy liver transplant donors; H&E, Masson, Perls Prussian blue, and immunohistochemical staining were performed. Compared with healthy Con, BMI, SBP, and DBP were significantly increased, and ALT, AST, TC, TG, LDL-C, GLU, HbA1c, INS, Hcy, and UA levels were all significantly increased, while HDL-C levels were decreased in MAFLD patients (MAFLD vs. Con, p < 0.05 or p < 0.001). Serum levels of ANGPTL7, TNF-α, IL-6, ACSL4, Keap-1, HO-1, and ferritin were significantly increased, while IL-10, GPX4, and Nrf2 levels were decreased in MAFLD patients when compared with the Con group (MAFLD vs. Con, all p < 0.001). Immunohistochemical staining showed that the expression of ANGPTL7, Keap-1, and HO-1 was significantly increased, while Nrf2 expression was significantly decreased in liver tissue from the MAFLD group (MAFLD vs. Con, all p < 0.05). ROC analysis showed that the optimal cut-off value of serum ANGPTL7 for MAFLD was 9.75 ng/mL, suggesting it could serve as a potential biomarker for the diagnosis of MAFLD. ANGPTL7 may participate in the pathogenesis of MAFLD, and serum ANGPTL7 has predictive value for the diagnosis of MAFLD.
In Vitro Biological Activities of Piper corcovadensis C.DC.: Antioxidant, Antineoplastic-Related and Antibacterial Effects.
Fontoura BH, Perin EC, Bagatini MD … +5 more , Manica D, da Silva GB, Rodrigues MFF, Marchese JA, Carpes ST
FASEB J · 2026 Jun · PMID 42247280 · Full text
Oxidative stress, caused by excessive reactive oxygen (ROS) and nitrogen species (NOX), is linked to degenerative, inflammatory, and cancer-related conditions. Piper corcovadensis, a South American native plant, is recog...
Oxidative stress, caused by excessive reactive oxygen (ROS) and nitrogen species (NOX), is linked to degenerative, inflammatory, and cancer-related conditions. Piper corcovadensis, a South American native plant, is recognized for its bioactive compounds. This study investigated the total phenolic content (TPC) by the Folin-Ciocalteu method, antioxidant activity (AA), cytotoxicity, and antimicrobial and anti-inflammatory effects of its extract. AA was determined by the ABTS, DPPH, and FRAP assays. Cytotoxicity was evaluated on SK-MEL-28 melanoma cells through the MTT assay. Oxidative stress biomarkers (ROS, NOX), protein thiols (PSH), and non-protein thiols (NPSH) and inflammatory mediators (NLRP3, IL-6, TNF) were analyzed by RT-qPCR at 50, 500, and 5000 μg mL. Antibacterial activity against Bacillus subtilis, Escherichia coli, Listeria monocytogenes, and Salmonella Typhimurium was assessed using MIC and MBC. The extract showed 11.64 mg GAE g and AA of 33.15 mM Trolox g (ABTS), and 21.27 mM Trolox g (DPPH). At 500 and 5000 μg mL, it reduced SK-MEL-28 viability and decreased ROS, NOX, and PSH. At 5000 μg mL, it downregulated NLRP3 and IL-6 while upregulating TNF. MIC and MBC were > 5 mg mL for all strains and showed no antibacterial activity at the tested concentrations. However, the extract of Piper corcovadensis exhibits significant in vitro bioactivity, particularly in antioxidant capacity, modulation of oxidative stress markers, and effects on melanoma cell viability.
SENP3 Exacerbates Spinal Cord Injury by Increasing H6PD deSUMOylation to Promote Glycolysis.
Jiang N, Tang Y, Gui YC … +4 more , Yao JZ, Fang CN, Song T, Xu JW
FASEB J · 2026 Jun · PMID 42247250 · Publisher ↗
Spinal cord injury (SCI) leads to persistent neurological deficits in patients, and effective clinical interventions remain limited. This study aims to elucidate the role and regulatory mechanisms of H6PD in SCI progress...
Spinal cord injury (SCI) leads to persistent neurological deficits in patients, and effective clinical interventions remain limited. This study aims to elucidate the role and regulatory mechanisms of H6PD in SCI progression, thereby providing insights for developing novel therapeutic strategies. Functional recovery after SCI was assessed using BBB scores, inclined plane tests, and rotarod tests. Spinal cord pathology was evaluated through HE and Nissl staining. The ECAR and OCR were measured using the Seahorse XF96 analyzer. Intracellular ROS levels were detected with DCFH-DA fluorescent probes. Lactate levels, NADPH/NADP ratios, and the levels of MDA, GSH, and SOD were determined using commercial kits. Apoptosis was analyzed by flow cytometry. Protein interactions and SUMOylation levels were examined by Co-IP. H6PD was compensatorily upregulated in SCI rats. H6PD knockdown aggravated neurological deficits and tissue damage. In HO-induced primary neurons, H6PD knockdown enhanced glycolysis, oxidative damage, and apoptosis. Mechanistically, SENP3 interacted with H6PD and promoted its deSUMOylation to inhibit its protein stability. Furthermore, SENP3 exacerbated HO-induced neuronal oxidative damage, apoptosis, and glycolytic abnormalities by downregulating H6PD and disrupting the SIRT1/HIF-1α pathway. SENP3 aggravated neuronal injury and glycolytic dysfunction in SCI by promoting H6PD deSUMOylation and impairing the SIRT1/HIF-1α pathway.
TurboID-Based Proximity Labeling Map Reveals the Protein Interaction Network and Anti-Viral Mechanism Against Influenza A H1N1.
Wang M, Wang Z, Liu C … +4 more , Duan J, Wu T, Fu Q, Su X
FASEB J · 2026 Jun · PMID 42247242 · Publisher ↗
Influenza A virus (IAV) remains a significant public health threat due to its high variability and pathogenicity. Systematic identification of viral-host interfaces is critical for developing targeted therapies. In the p...
Influenza A virus (IAV) remains a significant public health threat due to its high variability and pathogenicity. Systematic identification of viral-host interfaces is critical for developing targeted therapies. In the present study, TurboID proximity labeling was applied to map interactomes of 10 H1N1 viral proteins in human alveolar epithelial cells A549. Key interactions were validated via co-immunoprecipitation (Co-IP), confocal microscopy, dual-luciferase reporter assays, and functional studies. Results showed that Hemagglutinin (HA) and polymerase acidic (PA) directly bound mitochondrial antiviral-signaling protein (MAVS), significantly suppressing interferon-beta (IFN-β) promoter activity and impairing phosphorylation of TANK-binding kinase 1 (TBK1)/signal transducer and activator of transcription (STAT) signaling proteins. HA exploited integrin alpha-2 (ITGA2) as a novel entry cofactor, with their interaction confirmed by bidirectional Co-IP and co-localization. ITGA2 silencing markedly reduced viral titers. Tripartite motif-containing protein 56 (TRIM56) restricted H1N1 replication by binding viral nucleoprotein (NP) and inducing proteasomal degradation via K48-linked ubiquitination. As a conclusion, this study delineates H1N1's coordinated tactics to hijack host pathways, identifying MAVS, ITGA2, and TRIM56 as pivotal nodes for combination therapies. TurboID-driven interactomics provides a promising framework for system-level antiviral discovery.
Cathepsin S Deficiency Prevents Chronic Stress-Related Renal Remodeling and Dysfunction in a Mouse 5/6 Nephrectomy Injury Model.
Wang H, Xu S, Meng X … +12 more , Wan Y, Piao L, Inoue A, Kumar V, Fang E, Liu B, Shi GP, Kuzuya M, Umegaki H, Jin X, Yue X, Cheng XW
FASEB J · 2026 Jun · PMID 42247209 · Publisher ↗
Chronic psychological stress exacerbates chronic kidney disease (CKD). Given that lysosome cathepsins participate in human pathobiology, we investigated the roles of cathepsin S (CatS) in chronic stress-related renal dam...
Chronic psychological stress exacerbates chronic kidney disease (CKD). Given that lysosome cathepsins participate in human pathobiology, we investigated the roles of cathepsin S (CatS) in chronic stress-related renal damage and dysfunction in mice subjected to a 5/6 nephrectomy surgery. A mouse model combining 5/6 nephrectomy (5/6Nx) surgery and chronic restrain stress (CRS) was applied to wild-type (CatS) and CatS knockout (CatS) mice. The CRS exacerbated the 5/6Nx-induced renal injury, blood-pressure elevation, glomerulosclerosis, fibrosis, podocyte damage, and inflammatory macrophage infiltration while simultaneously increasing the renal CatS expression. Compared to the CatS mice, the CatS mice exhibited attenuated CRS-induced renal injury exacerbation manifested by improved renal function (urinary albumin) and blood pressure, reduced microstructure alterations, and lowered levels of renal inflammation (interleukin-1β, tumor necrosis factor-α, galectin-3, angiotensin II type 1 receptor, monocyte chemoattractant protein-1, and Toll-like receptor-2), oxidative stress (gp91, p22)-related and apoptosis [cleaved caspase-3 (C-caspase-3), cytochrome c, and Bcl-2]-related, extracellular remodeling (CatS, matrix metalloproteinase-9, and collagen types I and III)-related molecular proteins and/or genes. Pharmacological inhibition of CatS yielded the same conclusions. In mesangial cells, CatS overexpression and silencing, respectively, elevated or lowered C-caspase-3 and cytochrome c levels, providing evidence that a mechanistic explanation of CatS-caspase-3/cytochrome-mediated cell apoptosis in response to 5% stressed serum and oxidative stress. CatS inhibition appeared to ameliorate CRS-related renal injury and hypertension development in mice that underwent 5/6 nephrectomy surgery, possibly by lowering renal oxidative stress, inflammation, proteolysis, and apoptosis. CatS might thus become a potential therapeutic target for CRS-related renal remodeling and hypertension in animals with CKD.
Tumor-Associated Neutrophils Secrete AGR2 to Promote Colorectal Cancer Progression by Stabilizing ALYREF to Boost Snail m5C Modification.
Zeng W, Xiao J, Xie J … +1 more , Li Y
FASEB J · 2026 Jun · PMID 42241033 · Publisher ↗
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, primarily due to distant metastasis. Tumor-associated neutrophils (TANs), a major component of the tumor microenvironment (TME), pla...
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, primarily due to distant metastasis. Tumor-associated neutrophils (TANs), a major component of the tumor microenvironment (TME), play multifaceted roles in tumor progression. However, the molecular mechanisms by which TANs regulate epithelial-mesenchymal transition (EMT) in CRC remain unclear. This study aims to investigate how TANs promote CRC progression through EMT. CRC and paired adjacent normal tissues were collected for Western Blot, IHC, and flow cytometry to evaluate ALYREF and CD66b expression. NB-4 cells were induced with all-trans retinoic acid to generate TANs, and conditioned medium (TAN-CM) was collected for co-culture with CRC cells. Malignant phenotypes of CRC cells were assessed by CCK-8, EdU, and transwell assays. The m5C modification level and stability of Snail mRNA were determined by MeRIP and actinomycin D assays. Protein and RNA interactions were examined using Co-IP and RIP. A dual-luciferase reporter assay was used to evaluate the interaction between ALYREF and the m5C site in Snail mRNA. CHX assay was performed to assess ALYREF protein stability. A subcutaneous xenograft model with neutrophil depletion was established to validate the role of the AGR2-ALYREF-Snail axis in vivo, followed by HE staining and IHC analysis of tumor tissues. The infiltration of TANs was positively correlated with ALYREF expression in CRC. TAN-secreted AGR2 stabilized ALYREF, enhancing its recognition of m5C sites in Snail mRNA, thereby increasing Snail stability and promoting EMT. Blockade of AGR2 mitigated TAN-induced CRC cell proliferation, migration, and EMT, while ALYREF overexpression partially rescued these effects. In vivo, AGR2 overexpression promoted tumor growth and EMT through neutrophil-dependent activation of the ALYREF-Snail axis. TAN-secreted AGR2 enhances ALYREF stability, thereby promoting m5C-dependent Snail mRNA stabilization and sustaining EMT and CRC progression.
Retinoic Acid-Related Orphan Nuclear Receptor Alpha Promotes Cartilage Degeneration in Osteoarthritis by Activating the Wnt/β-Catenin Pathway.
Zhu R, He T, Di J … +7 more , Mai L, Wu D, Huang M, Liu Y, Liu Z, Zhang L, He L
FASEB J · 2026 Jun · PMID 42240585 · Publisher ↗
Osteoarthritis (OA) is the most common degenerative joint disease. Recent evidence has shown that retinoic acid-related orphan nuclear receptor alpha (RORα) plays an important role in OA pathogenesis. However, its downst...
Osteoarthritis (OA) is the most common degenerative joint disease. Recent evidence has shown that retinoic acid-related orphan nuclear receptor alpha (RORα) plays an important role in OA pathogenesis. However, its downstream regulatory mechanisms remain to be elucidated. Alterations in chondrocyte extracellular matrix (ECM) metabolism were observed by overexpressing or knocking down RORα in OA chondrocyte models. The OA mouse model was induced by unstable medial meniscus surgery (DMM), and the RORα inhibitor SR3335 or AAV virus was injected intra-articularly into the mice. Furthermore, Col2a1-creERT2: RORα (RORα-KO) inducible conditional knockout mice were generated to elucidate the role of RORα in OA. Moreover, mRNA sequencing was conducted to identify potential downstream regulatory mechanisms of RORα. The overexpression of RORα in chondrocytes induced ECM degradation in mouse chondrocytes and accelerated cartilage degeneration in mice. In contrast, treatment with SR3335 or knockdown of RORα in chondrocytes alleviated ECM degradation. Similarly, less cartilage degeneration was observed in intra-articular injections of SR3335 and in the RORα-KO mice. Mechanistically, cartilage degeneration was promoted by RORα through the activation of the Wnt/β-catenin pathway and the facilitation of the nuclear translocation of β-catenin. Notably, the Wnt/β-catenin pathway inhibitor XAV-939 ameliorated RORα-induced ECM degradation in chondrocytes. The expression of RORα is increased in OA, triggering an imbalance in cartilage ECM metabolism, which leads to cartilage degeneration. Notably, the Wnt/β-catenin signaling pathway plays a critical role in RORα-mediated regulation of ECM degradation in chondrocytes. In summary, the RORα-Wnt/β-catenin pathway axis is pivotal in the pathogenesis of OA.
Electroacupuncture Alleviates Pain and Anxiety in CFA-Induced Mice by Suppressing Glutamatergic Neurons in the Spinoparabrachial Pathway.
Ji Y, Ye R, He W … +9 more , Jiang Y, Guan L, Guo Z, He X, Liang Y, Shao X, Fang J, Fang J, Du J
FASEB J · 2026 Jun · PMID 42240472 · Publisher ↗
The spinoparabrachial tract is a major ascending pathway that transmits nociceptive signals from the spinal cord to the brain, but whether electroacupuncture (EA) relieves pain-anxiety comorbidity by modulating this path...
The spinoparabrachial tract is a major ascending pathway that transmits nociceptive signals from the spinal cord to the brain, but whether electroacupuncture (EA) relieves pain-anxiety comorbidity by modulating this pathway remains unclear. Here, we investigated the effects of EA on mechanical allodynia and anxiety-like behaviors in Complete Freund's adjuvant (CFA)-induced inflammatory pain mice using von Frey testing, the open field test, and the elevated plus maze, combined with chemogenetic manipulation of glutamatergic projections from the spinal dorsal horn (SDH) to the lateral parabrachial nucleus (LPBN). EA attenuated CFA-induced mechanical allodynia and anxiety-like behaviors and reduced c-Fos expression in both the SDH and LPBN. Chemogenetic inhibition of LPBN glutamatergic neurons mimicked the analgesic and anxiolytic effects of EA, whereas their activation abolished these effects. Activation of either ipsilateral or contralateral SDH→LPBN glutamatergic projections induced pain- and anxiety-like phenotypes that depended on intact LPBN glutamatergic output. Moreover, selective activation of spinoparabrachial glutamatergic terminals was sufficient to block the therapeutic efficacy of EA. These findings indicate that EA alleviates CFA-induced pain-anxiety comorbidity by inhibiting the SDH-LPBN glutamatergic circuit, identifying a key ascending pathway through which peripheral EA signals modulate central pain and affective processing.
Targeting Fatty Acid Synthase With Berberine Promotes IL-10 Production in Macrophages and Prevents Relapse in a Murine Colitis Model.
Hayashi S, Ogawa Y, Wakabayashi N … +6 more , Tokuyama K, Oku M, Yamamoto T, Kato S, Nusrat A, Kadowaki M
FASEB J · 2026 Jun · PMID 42240471 · Publisher ↗
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by alternating periods of remission and relapse. Current therapeutic options for maintaining long-term remission are limited, and no estab...
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by alternating periods of remission and relapse. Current therapeutic options for maintaining long-term remission are limited, and no established animal model exists for evaluating relapse. We hypothesized that enhancing interleukin-10 (IL-10) production in intestinal macrophages could serve as a novel therapeutic strategy. Through the screening of a library of natural compounds derived from medicinal herbs, we identified berberine as a promising IL-10 enhancer. This study aimed to develop an experimental relapse model and elucidate the mechanism through which berberine promotes IL-10 production. Male C57BL/6 mice were subjected to two cycles of dextran sulfate sodium (DSS) treatment to induce colitis relapse. Bone marrow-derived macrophages (BMDMs) were treated with berberine before LPS stimulation, and IL-10 levels were measured. Drug affinity responsive target stability (DARTS) analysis was used to identify berberine-binding proteins. Berberine increased IL-10 expression in the colons of treated mice and suppressed colitis relapse when it was administered during the recovery phase. Additionally, berberine promoted colonic mucosal wound repair in vivo. In vitro, berberine enhanced LPS-induced IL-10 secretion by BMDMs. DARTS analysis revealed fatty acid synthase (FASN) as a direct berberine-binding protein. The FASN inhibitor cerulenin and Fasn knockdown both attenuated berberine-induced IL-10 production, suggesting a FASN-dependent augmentation pathway. These findings indicate that berberine suppresses colitis relapse by enhancing IL-10 production in macrophages via FASN binding. Our study highlights the increase in IL-10 levels through FASN as a promising strategy for maintaining remission in patients with IBD.
Axin1 Suppresses Muscle Regeneration by Promoting Myoblast Proliferation and Inhibiting Differentiation.
Yue Y, Zhang C, Guo Y … +5 more , Zhang L, Gu Q, Zhou C, Mu H, Niu W
FASEB J · 2026 Jun · PMID 42233605 · Publisher ↗
Axin1, a scaffold protein, participates in maintaining glucose homeostasis and muscle function. However, the role of Axin1 in regulating skeletal muscle growth and regeneration remains poorly understood. This study aims...
Axin1, a scaffold protein, participates in maintaining glucose homeostasis and muscle function. However, the role of Axin1 in regulating skeletal muscle growth and regeneration remains poorly understood. This study aims to investigate the role of Axin1 in skeletal muscle proliferation, differentiation, and regeneration in the context of insulin resistance or obesity. We found that knockdown of Axin1 decreased the protein level of Cyclin D1 and increased the protein levels of MyoG and MyHC, but without effect on MyoD protein levels, to inhibit proliferation and promote differentiation of C2C12 muscle cells. Over-expression of Axin1 had the opposite effect. Chronic insulin treatment up-regulated Axin1 protein levels, which promoted myoblast proliferation and impaired differentiation in C2C12 muscle cells. Knockdown of Axin1 reversed these effects by inducing Cyclin D1-mediated cell cycle arrest and up-regulating MyoG expression. AAV-siAxin1 significantly increased the protein and mRNA levels of MyoG of basal and CTX-injured mouse skeletal muscle, without effect on Pax7 and MyoD. Skeletal muscle of HFD-fed mice and db/db mice have higher Axin1 and lower MyoG, eMyHC, and Desmin protein levels, which correlated with reduced early muscle regeneration in injured muscle. Knockdown of Axin1 reversed the effect of HFD on muscle regeneration. In summary, down-regulation of Axin1 inhibits muscle cell proliferation and promotes differentiation in basal and insulin resistant conditions, and promotes skeletal muscle regeneration in HFD mice.
Disease-Associated Remodeling of m6A RNA Methylation in Human Interstitial Cells From Fibro-Calcific Aortic Valves.
Valerio V, Molla O, Massaiu I … +4 more , Garoffolo G, Myasoedova VA, Chiesa M, Poggio P
FASEB J · 2026 Jun · PMID 42233580 · Publisher ↗
Calcific aortic valve disease is common in older adults and a major cause of aortic stenosis. Despite its clinical impact, there are still no effective drugs that slow disease progression, and treatment largely relies on...
Calcific aortic valve disease is common in older adults and a major cause of aortic stenosis. Despite its clinical impact, there are still no effective drugs that slow disease progression, and treatment largely relies on surgical or transcatheter valve replacement once stenosis becomes severe and symptomatic. Beyond established roles for inflammation and tissue remodeling, recent evidence suggests that chemical modifications of RNA may influence how valve cells shift toward fibro-calcific states. In this study, we compared human valvular interstitial cells isolated from non-calcified valves and from fibro-calcific stenotic valves, profiling RNA modifications using direct RNA sequencing. The resulting epitranscriptomic patterns clearly separated control from diseased cells and revealed an overall increase in detected modification sites in disease, alongside site-specific gains and losses across selected transcripts. Network-based prioritization highlighted genes linked to extracellular matrix remodeling and inflammatory signaling, pointing to stress-responsive regulators as notable candidates. Overall, these findings support the idea that disease-associated RNA modification remodeling accompanies, and may help shape, key cellular programs in calcific valve disease, providing a focused set of targets for future functional validation and potential non-surgical therapeutic exploration.
Melatonin Accelerates Diabetic Wound Repair via Modulation of Tenascin C and Interleukin-10 in Fibroblasts.
Sun J, Qian Y, Chen S … +7 more , Zhou M, Yu Y, Wang L, Huang X, Chen X, Zhang C, Sun J
FASEB J · 2026 Jun · PMID 42233548 · Publisher ↗
A central pathophysiological driver of chronic skin wounds in patients with diabetes and other comorbidities is the dysregulation of the local wound microenvironment, characterized by compromised fibroblast functionality...
A central pathophysiological driver of chronic skin wounds in patients with diabetes and other comorbidities is the dysregulation of the local wound microenvironment, characterized by compromised fibroblast functionality, insufficient extracellular matrix synthesis, and sustained inflammatory dysregulation. Previous studies have revealed that melatonin plays an indispensable role in safeguarding skin structural integrity and sustaining cutaneous homeostasis. However, the role of melatonin in chronic skin wounds associated with diabetes remains poorly understood. In this study, utilizing db/db mouse skin trauma models and in vitro cultures of human dermal fibroblasts (HDF) exposed to advanced glycation end products (AGEs), we established that melatonin robustly augmented granulation tissue formation in db/db mouse skin wounds, consequently expediting in vivo wound healing. Concomitantly, melatonin enhanced the wound reparative capacity of AGEs-treated HDF and stimulated fibroblast proliferation through canonical melatonin receptors (MT1/MT2), while abrogating their differentiation into myofibroblasts and mitigating pro-inflammatory responses. Moreover, RNA-sequencing and functional analyses elucidated that the pro-repair effects of melatonin on skin wounds were mechanistically linked to its modulation of tenascin C and interleukin-10. Collectively, this work thus paves the way for the translational application of melatonin in treating diabetic-associated chronic wounds.
Cannabigerol Alleviates Obesity-Induced Mitochondrial Dysfunction by Cardiolipin Fatty Acid Remodeling.
Bielawiec P, Konstantynowicz-Nowicka K, Chabowski A … +1 more , Harasim-Symbor E
FASEB J · 2026 Jun · PMID 42233524 · Publisher ↗
Until now, strategies to offset the harmful effects of obesity using phytocannabinoids have only begun to be unraveled. Therefore, we aimed to identify the possible therapeutic role of 2-week cannabigerol (CBG) treatment...
Until now, strategies to offset the harmful effects of obesity using phytocannabinoids have only begun to be unraveled. Therefore, we aimed to identify the possible therapeutic role of 2-week cannabigerol (CBG) treatment on intramuscular fatty acids (FAs) and lipid metabolism, with subsequent implications for mitochondrial cardiolipin composition in male Wistar rats in the context of a high-fat, high-sucrose diet-induced obesity. To elucidate underlying mechanisms, we assessed expression and cellular localization of fatty acid-handling proteins, intramuscular lipid profile, the total expression of proteins involved in FAs synthesis and metabolism, cardiolipin content and composition, cytochrome c oxidase activity, as well as superoxide dismutase (SOD) level and lipid peroxides formation using Western blotting, gas-liquid chromatography, and immunoenzymatic kits. Our findings demonstrate that CBG alleviates obesity-induced recruitment of fatty acid transporters to the plasma membrane, thereby limiting intracellular FAs influx and protecting myocytes against excess lipogenesis and subsequent lipid storage. Moreover, we also revealed obesity-related defective cardiolipin fatty-acyl chain remodeling, characterized by excess accumulation of docosahexaenoic acid, leading to increased unsaturated aldehyde formation. Importantly, CBG upregulated muscular cardiolipin and prevented the buildup of C22:6n-3, which was accompanied by elevated SOD levels and reduced formation of lipid peroxidation products, indicating enhanced cellular antioxidant defense. Hence, CBG-mediated effects may fulfill an urgent, so far unmet clinical need for treatments that can directly target muscular obesity-associated metabolic defects.
Compartment-Specific Immune Remodeling of Renal Aging With C1q-Associated Podocyte Activation.
Moon JY, Shim K, Lim HJ … +8 more , Kim DK, Moon YY, Jung SW, Kim YG, Kang H, Lee TH, Lee JH, Lee SH
FASEB J · 2026 Jun · PMID 42228587 · Publisher ↗
Despite progress in distinguishing glomerular and non-glomerular functions, lifespan transcriptional changes, and how aging differs from CKD adaptation remain unclear. Using RNA sequencing, we performed transcriptional a...
Despite progress in distinguishing glomerular and non-glomerular functions, lifespan transcriptional changes, and how aging differs from CKD adaptation remain unclear. Using RNA sequencing, we performed transcriptional analyses of glomerular compartments, non-glomerular compartments, and whole kidneys from 2-, 12-, and 24-month-old mice. Aging consistently activated immune and inflammatory programs across all parts, yet each displayed distinct immune signatures and immune cell infiltration patterns. Glomerular aging was characterized by a prominent increase in podocyte complement pathway activity, especially C1q expression. In aged podocytes, C1q stimulation was associated with enhanced chemokine expression and phagocytic activity. Tubulointerstitial aging featured marked B cell aggregation and expansion of tertiary lymphoid structures. In renal aging, the major long noncoding RNAs were 5430416N02Rik, Aw112010, and Mir142hg, which were associated with proliferation and immune responses. Comparative analyses with injured fibrotic kidneys revealed differential regulation of adaptive immune cells as a principal discriminator between physiologic aging and chronic kidney disease (CKD) adaptation. These results suggest that aging repatterns the renal immune response in a functional site-specific manner and is distinct from CKD-associated remodeling.
Structural Control of NLRP3 Inflammasome Assembly and the Emerging Microprotein Frontier.
Hamad RS, Suliman SAA, Kadhim ME … +8 more , Hasan WA, Elmorsy EA, Hamza E, Ibrahim EAA, Mohamed RMS, Eissa H, Farrag AA, Saber S
FASEB J · 2026 Jun · PMID 42228549 · Publisher ↗
The NLRP3 inflammasome responds to chemically and biologically diverse stimuli, yet growing evidence indicates that this apparent diversity converges on a limited set of structural and spatial licensing steps. Here, we a...
The NLRP3 inflammasome responds to chemically and biologically diverse stimuli, yet growing evidence indicates that this apparent diversity converges on a limited set of structural and spatial licensing steps. Here, we argue that NLRP3 regulation is best understood through an assembly-centered framework rather than as another stimulus-centered catalog of activators. Cryo-electron microscopy (Cryo-EM), biochemical, and cell-biological studies support a model in which NLRP3 is maintained in inactive cage-like assemblies, undergoes nucleotide-dependent conformational rearrangements, engages NEK7, and nucleates ordered supramolecular complexes containing apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). We synthesize current evidence for structural licensing, interface-level restraint, subcellular trafficking, phase-separation-linked organization, and post-translational and proteostatic control of NLRP3 assembly. We then examine a less explored question with translational implications: whether peptide-scale regulators, particularly endogenous microproteins, may control defined assembly transitions. Available evidence supports the existence of synthetic peptides that inhibit inflammasome interfaces and of endogenous microproteins that intersect with inflammatory signaling. However, direct evidence that endogenous microproteins act as dedicated interface-mimic inhibitors of NLRP3 assembly remains lacking. This review integrates mature structural models of NLRP3 regulation with the emerging microprotein field while clearly distinguishing established mechanisms from plausible but unproven hypotheses. This perspective defines a mechanistically explicit agenda for future work, including rigorous validation of translated small open reading frames (smORFs), direct interaction mapping to defined NLRP3 surfaces, and quantitative testing of effects on assembly, signaling output, and cellular context.
Synergistic Renoprotective Effects of Moderate-Intensity Resistance Training and Vitamin D Supplementation on a Type 2 Diabetic Nephropathy Rat Model.
Liu J, Wu C, Zou Q … +3 more , Li C, Sun X, Zhao L
FASEB J · 2026 Jun · PMID 42227748 · Publisher ↗
Vitamin D (VD) supplementation and resistance exercise synergistically improve diabetic nephropathy in type 2 diabetes mellitus (T2DM). However, the effects of varying exercise intensities and underlying mechanisms remai...
Vitamin D (VD) supplementation and resistance exercise synergistically improve diabetic nephropathy in type 2 diabetes mellitus (T2DM). However, the effects of varying exercise intensities and underlying mechanisms remain unclear. This study systematically examined the combined effects of low-intensity resistance training with VD (LRV), moderate-intensity resistance training with VD (MRV), and high-intensity resistance training with VD (HRV) in a T2DM rat model. We aimed to determine the optimal exercise intensity combined with VD supplementation and elucidate its associated molecular mechanisms. All combined interventions significantly improved glucose metabolism and insulin sensitivity, with the most pronounced effects observed in the MRV group. MRV was most effective in restoring renal function, as indicated by reductions in blood urea nitrogen and serum creatinine. MRV also significantly inhibited diabetes-induced renal fibrosis and inflammation, demonstrated by decreased TNF-α, IL-1β, and IL-6 levels. Mechanistically, MRV upregulated renal VD receptor (VDR) expression and inhibited the p38 mitogen-activated protein kinase (MAPK) and ERK1/2 signaling pathways, resulting in reduced renal fibrosis and local inflammation. Comparative analysis indicated that MRV produced the most effective synergistic outcome, with an optimal intensity threshold. These results suggest that MRV is a potential non-pharmacological strategy to alleviate complications of type 2 diabetes via the VDR-MAPK signaling pathway, with important implications for clinical exercise prescription.
TNFSF15 Promotes Vascular Normalization and Tertiary Lymphoid Structure Formation in Experimental Ovarian Cancer.
Wang JY, Wang YY, Zhang LS … +4 more , Weng ST, Cui HY, Zhang ZS, Li LY
FASEB J · 2026 Jun · PMID 42227655 · Publisher ↗
Diminished lymphocyte infiltration and activation in ovarian cancer are attributable to the malignancy and irresponsiveness to immunotherapy. We show here that treatment of a murine model of ovarian cancer with recombina...
Diminished lymphocyte infiltration and activation in ovarian cancer are attributable to the malignancy and irresponsiveness to immunotherapy. We show here that treatment of a murine model of ovarian cancer with recombinant tumor necrosis factor superfamily-15 (TNFSF15) results in a marked inhibition of peritoneal dissemination of the cancer cells and a substantial reduction of ascites. The treatment leads to normalization of the tumor vasculature judged by enhanced coverage of the neo-blood vessels with PDGFβ pericytes and diminished levels of the hypoxia-responsive cancer stem cell marker CD133. Additionally, the treatment gives rise to accumulation of Lyve-1 lymphatic endothelial cells and PNAd high endothelial venules (HEV) in the tumors, consistent with the formation of tertiary lymphoid structures (TLS). Moreover, the treatment results in facilitated tumor infiltration of T cells, B cells, macrophages, and dendritic cells, the latter exhibit upregulated expression of TLS-associated cytokines and chemokines, including Lt-α, Lt-β, IFN-β, TNF-α, CCL19, CCL21, CXCL13, and CXCL10. Furthermore, there is an enhanced responsiveness in TNFSF15-treated tumors toward PD-1 blockade treatment. These findings suggest that TNFSF15 is capable of facilitating vascular normalization and TLS formation, and thus promoting a reinstitution of the immune microenvironment in ovarian cancer.
COX-2-Derived PGE Modulates IL-17 Production by γδ T Cells During Allergic Lung Inflammation.
Feng C, Li H, Menendez D … +8 more , Edin ML, Gruzdev A, Graves JP, DeGraff LM, Xu X, Bennett BD, Li JL, Zeldin DC
FASEB J · 2026 Jun · PMID 42223986 · Publisher ↗
Cyclooxygenase-2 (COX-2)-derived prostaglandins (PGs) regulate differentiation of αβ T helper cells to Th2, Th9, and Th17 cell subsets during allergic lung inflammation. IL-17, the signature cytokine of Th17 cells, is a...
Cyclooxygenase-2 (COX-2)-derived prostaglandins (PGs) regulate differentiation of αβ T helper cells to Th2, Th9, and Th17 cell subsets during allergic lung inflammation. IL-17, the signature cytokine of Th17 cells, is a critical regulator of allergic immunopathology. Most studies on IL-17 have focused on Th17 cells, though T cells are the primary IL-17-producing lymphocyte subset. Unlike conventional αβ T cells, T cells preferentially colonize non-lymphoid tissues, such as intestine and airway epithelia/mucosa. It remains unknown if COX-2-derived PGs regulate T cells during allergic lung inflammation. Herein, we examined how COX-2-derived PGs regulate T cells using in vivo and in vitro assays with COX-2 and COX-2 mice and isolated T cells. COX-2 disruption reduced bronchoalveolar lavage fluid (BALF) IL-17A production during ovalbumin (OVA)-induced allergic lung inflammation in vivo without altering the number of IL-17A-producing T cells. Isolated T cells produced IL-17A upon restimulation with IL-1β + IL-23 ex vivo; however, T cells from COX-2 mice produced less IL-17A than T cells from COX-2 mice. Of multiple PGs tested, only PGE significantly promoted IL-1β + IL-23-induced IL-17A production by T cells. Single cell RNA sequencing (scRNA-seq) identified, and qPCR confirmed, that T cells express only two PGE receptors (EP2 and EP4). Both EP2 and EP4 antagonists attenuated the PGE-mediated increases in IL-17A formation by T cells. Taken together, these data suggest that COX-2-derived PGE enhances IL-17A production in T cells in an EP2/EP4 dependent manner during allergic lung inflammation.
Polyphosphates Attenuate Interleukin-12 Production in Macrophages Infected With Legionella pneumophila.
Vasilew K, Jayaraman A, Platten J … +10 more , Xu S, Josinsky S, Roewe J, Mimmler M, Kilroy J, Echahidi F, Kaya Z, Zamboni DS, Reinhardt C, Bosmann M
FASEB J · 2026 Jun · PMID 42219888 · Publisher ↗
Polyphosphates are evolutionarily conserved linear chains of phosphate residues present in all living cells. Bacteria accumulate polyphosphates under stress and starvation for energy and phosphate storage, protein foldin...
Polyphosphates are evolutionarily conserved linear chains of phosphate residues present in all living cells. Bacteria accumulate polyphosphates under stress and starvation for energy and phosphate storage, protein folding, and stress adaptation. During infection, bacteria release polyphosphates that may impair host responses, although the exact mechanisms remain elusive. In this study, polyphosphates were found to be elevated in bronchoalveolar lavage fluids from patients with Legionnaires' disease, in Legionella pneumophila cultured alone, or during infection of bone marrow-derived macrophages (BMDMs) from C57BL/6J mice. We performed RNA-sequencing of infected BMDMs co-incubated with or without long-chain, bacterial-type polyphosphates. Among nearly 500 differentially expressed genes, Il12b (p40) showed the strongest suppression among highly expressed genes. IL-12p40 protein release was dose-dependently reduced by long-chain polyphosphates (~P700), but not by short-chain, mammalian-type polyphosphates (~P70), indicating a specific bacterial mechanism targeting innate immune signaling. In contrast, IL-18, processed by inflammasome activation and synergizing functionally with IL-12, was not consistently suppressed. Polyphosphates predominantly inhibited LPS/TLR4 signaling, with Legionella-induced IL-12 relying on the MyD88 pathway, but not TRIF. RAGE and P2Y1, previously implicated in polyphosphate biology, were not required for IL-12 suppression. However, PI3K/AKT signaling appeared to mediate polyphosphate effects, which were reversed by the PI3K inhibitors, LY294002, copanlisib, and eganelisib. Finally, long-chain polyphosphates suppressed IL-12 release also from human monocyte-derived macrophages exposed to L. pneumophila or LPS. In summary, our findings identify a selective inhibition of IL-12 by long-chain bacterial polyphosphates, suggesting that these molecules act as bacterial effectors capable of suppressing protective innate immune responses.
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