FASEB Journal[JOURNAL]
Sun
200 papers
Ketogenic Diet Might Regulate Autophagy of BMSCs via mTOR Signaling Contributing to Osteoporosis in Mice.
Liu Q, Yang Z, Ye Y … +6 more , Li RY, Fan X, Lin H, Wang Y, Wu X, Zhu Q
FASEB J · 2026 May · PMID 42186781 · Publisher ↗
Rapamycin (Rapa), an mTOR inhibitor, enhances autophagy to alleviate bone loss in senile and estrogen-deficient osteoporosis by restoring the biological properties of bone marrow stromal cells (BMSCs). However, Rapa agai...
Rapamycin (Rapa), an mTOR inhibitor, enhances autophagy to alleviate bone loss in senile and estrogen-deficient osteoporosis by restoring the biological properties of bone marrow stromal cells (BMSCs). However, Rapa against bone loss induced by ketogenic diet (KD) and the underlying mechanism remain elusive. This study aims to evaluate Rapa's influence on KD-induced osteoporosis and clarify its underlying mechanisms. Microarchitectures of bone, serum concentrations of bone alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), along with osteocalcin (OCN), microtubule-associated protein light chain 3 (LC3), TRAP, and Sca-1 immunohistochemistry staining were evaluated in Sham, the OVX (ovariectomy), the OVX+ Rapa, the KD, and the KD+ Rapa groups. Expression of mTOR and the autophagy-related proteins, including LC3-II/LC3-I, Beclin1, ATG7, and P62 were also analyzed. Both KD and OVX induced significant bone loss in the cancellous bone of the distal femur and the L5 vertebra. Furthermore, KD effectively decreased serum ALP and increased TRAP in mice. In addition, KD and OVX downregulated OCN, ALP, RUNX2, the autophagy-related proteins, upregulated TRAP, PPARγ, p-mTOR, and P62, and decreased LC3 and Sca-1 expressions in mice. On the other hand, Rapa reduced significant bone loss in cancellous bone induced by KD or OVX. Additionally, Rapa effectively increased serum ALP and decreased TRAP in KD mice and decreased serum TRAP in OVX mice. It upregulated OCN, ALP, RUNX2, LC3-II/LC3-I, Beclin1, and ATG7 and downregulated TRAP, PPARγ, p-mTOR, and P62 in the KD and OVX cohorts. The findings demonstrated that autophagy downregulation might contribute to KD-induced osteoporosis, which may be part of the pathogenic mechanism responsible for bone loss during KD.
Ketogenic Diet Modulates Depressive-Like Behavior via Gut Bacterial Metabolism of Tyrosine.
Zhang Y, Li X, Zhang X … +6 more , Wang Y, Chen Z, Lin X, Zheng X, Hao H, Zhang X
FASEB J · 2026 May · PMID 42186771 · Publisher ↗
Emerging evidence suggests the therapeutic potential of ketogenic diet (KD) for mood disorders such as depression, yet the underlying mechanisms are poorly understood. Here we report a gut microbe-to-brain signaling path...
Emerging evidence suggests the therapeutic potential of ketogenic diet (KD) for mood disorders such as depression, yet the underlying mechanisms are poorly understood. Here we report a gut microbe-to-brain signaling pathway through which KD protects against depressive-like behavior in mice. We show that KD feeding triggers a prompt and dynamic remodeling of the gut microbiome, the depletion of which abrogates the protective effect of KD against depressive-like behavior in stressed mice. Colonization with Roseburia intestinalis (R. intestinalis), which is enriched by 1-week KD, sustains the protective effect of KD against depressive-like behavior in mice. The protective effect of KD is linked to the reduction of a host-microbe co-metabolite p-Cresol sulfate (p-CS), the supplementation of which negates the protective effect of KD against depressive-like behavior. Mechanistically, p-CS enters the brain and activates lateral habenula (LHb) to counteract the protective effect of KD. Our findings uncover a gut microbiota-brain axis mechanism for KD consumption to protect against depressive-like behavior.
NK Cells Promote Macrophage Foam Cell Formation via TIGIT/CD155-Mediated Cholesterol Metabolism.
Li J, Lian Z, Huang Q … +4 more , Zhao C, Wang G, Shi J, Shao D
FASEB J · 2026 May · PMID 42186763 · Publisher ↗
Macrophage foaming, characterized by uncontrolled uptake of oxidized LDL (ox-LDL) by macrophages, critically drives atherosclerosis (AS) progression. Although NK cells are found to be atherogenic, their direct impact on...
Macrophage foaming, characterized by uncontrolled uptake of oxidized LDL (ox-LDL) by macrophages, critically drives atherosclerosis (AS) progression. Although NK cells are found to be atherogenic, their direct impact on macrophage foaming remains unknown. Here we examined the role of NK cells in macrophage foaming and found that NK cells exacerbated macrophage cholesterol accumulation both in the presence/absence of ox-LDL. Under ox-LDL exposure, NK cells promoted cholesterol accumulation via increasing cholesterol influx related gene CD36, and significantly reducing the expressions of cholesterol efflux associated receptors ABCA1 and ABCG1 in the macrophages. When without ox-LDL, NK cells accelerated cholesterol synthesis via the SREBP-2-LDLR/HMGCR pathway, and inhibited cholesterol efflux via the LXR-α-ABCA1/ABCG1 pathway of macrophages. These factors eventually led to the accumulation of cholesterol in macrophages, resulting in the formation of macrophage foam cells. Further, for the first time, we revealed the TIGIT/CD155 signaling pathway as a critical regulatory mechanism for macrophage foam cell formation. Specifically, the downregulation of TIGIT in highly active NK cells altered its interaction with CD155, which influenced macrophage cholesterol metabolism via CD155 and ultimately promoted foam cell formation. Furthermore, direct blockade of CD155 on macrophages exacerbated cholesterol accumulation, thereby establishing CD155 as an important regulator in macrophage-derived foam cell formation. These findings not only confirm NK cells as important drivers of macrophage foam cell formation but also highlight CD155 as a potential therapeutic target for atherosclerosis.
Role of Brown Adipose Tissue-Specific Sympathetic and Sensory Innervations in Menthol-Induced Energy-Expending Phenotype.
Lal R, Soni N, Agarwal K … +8 more , Kondepudi KK, Khare P, Zimmermann K, Karbownik-Lewińska M, Gesing A, Aggarwal V, Chopra K, Bishnoi M
FASEB J · 2026 May · PMID 42186762 · Publisher ↗
Menthol, a TRPM8 agonist and pharmacological cold mimic, activates brown adipose tissue (BAT) to increase adaptive thermogenesis and whole-body energy expenditure. BAT is highly innervated with sensory and sympathetic ne...
Menthol, a TRPM8 agonist and pharmacological cold mimic, activates brown adipose tissue (BAT) to increase adaptive thermogenesis and whole-body energy expenditure. BAT is highly innervated with sensory and sympathetic nerve fibers. There is existing literature that sympathetic nerves have a critical role in regulating menthol's (or cold) effect on energy homeostasis, but there is minimal literature about the involvement of somatosensory innervations. Here, we ought to investigate whether short-term topical application (3 days) of menthol elicits sympathetic and sensory nerves. We used chemical denervation models of complete (100 mg/kg; 6-OHDA and 125 mg/kg; capsaicin, s.c.) and localized (in BAT, 20 μL of 6-OHDA (20 mg/mL) and 20 μL of capsaicin (20 μg/μL) in each BAT lobe) ablation of sympathetic (6-OHDA) and sensory (capsaicin) innervations to explore their roles in menthol induced BAT activation and energy expanding phenotype. In the present study we have shown that (i) short-term topical application of menthol (10% menthol for 3 consecutive days) elicits sympathetic and sensory innervations, and induces thermogenesis, lipolysis and mitochondrial biogenesis in mice BAT; (ii) localized ablation of sympathetic innervation prevented menthol induced BAT activation and lipolysis (iii) localized ablation of sensory neurons augments sympathetic innervations induced BAT activation and modulated thermoregulation. Collectively, our findings indicate that the sympathetic nervous system plays a major role in BAT activation following short-term topical menthol application. Furthermore, sensory neurons contribute partially to this effect.
Multi-Omics Identified Factor V Leiden as a Novel Predictor of 90-Day Mortality in Artificial Liver-Supported ACLF: A Translational Study.
Zhao W, Ruan H, Li L … +8 more , Qiao Y, Wang Q, Dong Y, Luo Y, Liu F, Liu C, Zhao J, Li D
FASEB J · 2026 May · PMID 42186733 · Publisher ↗
This study employed integrated transcriptomic and proteomic analyses to identify clinically actionable prognostic biomarkers in patients with acute-on-chronic liver failure (ACLF) supported by an artificial liver support...
This study employed integrated transcriptomic and proteomic analyses to identify clinically actionable prognostic biomarkers in patients with acute-on-chronic liver failure (ACLF) supported by an artificial liver support system (ALSS). For parallel transcriptomic and proteomic characterization, peripheral blood mononuclear cells (PBMCs) were extracted from 15 patients with hepatitis B virus (HBV)-associated ACLF and 4 healthy subjects. Clinical utility was assessed using an independent validation cohort comprising 70 patients with ACLF and 60 age and sex-matched healthy controls. A precision prognostic tool for mortality prediction was developed and validated using Lasso regression, logistic regression, and receiver operating characteristic (ROC) curve analysis. Multi-omics screening revealed 17 molecules with concordant RNA-protein alterations, among which coagulation factor V (F5) and related proteins showed dynamic expression during ALSS treatment. Validation in an independent cohort confirmed significantly elevated mRNA and plasma levels of factor V Leiden (FVL) in ACLF patients versus controls. Lasso and multivariate logistic regression identified baseline plasma FVL and its changes during treatment as independent predictors of 90-day mortality. The model combining baseline FVL and its dynamic changes achieved an AUC of 0.977 for mortality prediction. FVL represents a robust prognostic biomarker in ACLF. Integration of baseline quantification and treatment-responsive dynamics enables precise prediction of mortality risk.
METTL14 Regulates Adipose Tissue Macrophage Polarization via JAK2/STAT3 Pathway to Attenuate Obstructive Sleep Apnea-Related Systemic Inflammation.
Zhang Y, Zhao ZH, Li C … +6 more , Sun X, Guo R, Liu H, Li Y, Wang Y, Zou J
FASEB J · 2026 May · PMID 42186731 · Publisher ↗
The role of mA RNA methylation in obstructive sleep apnea (OSA)-related metabolic dysfunction and systemic inflammation is unknown. We aimed to identify the key mA regulator involved in OSA-induced adipose tissue inflamm...
The role of mA RNA methylation in obstructive sleep apnea (OSA)-related metabolic dysfunction and systemic inflammation is unknown. We aimed to identify the key mA regulator involved in OSA-induced adipose tissue inflammation and explore the underlying mechanisms. The expression of mA methylation regulators was measured and their associations with systemic inflammation indicators were analyzed in patients with OSA. A mouse model of OSA was established with high-fat diet feeding and chronic intermittent hypoxia (CIH) treatment. The histological alterations of epididymal white adipose tissue (eWAT) were evaluated. The effects and mechanisms of methyltransferase-like 14 (METTL14) on regulating macrophage polarization were determined by in vitro assays. The global mA RNA methylation levels and the expression levels of mA methylation regulators were altered in OSA patients. The mRNA expression level of METTL14 was negatively associated with systemic inflammation parameters. CIH treatment aggravated the infiltration of macrophages in the eWAT of mice. The mRNA and protein levels of METTL14 were downregulated in the eWAT of mice treated with CIH and in hypoxia-treated THP-1 macrophages. Overexpression of METTL14 was able to inhibit hypoxia-induced M1 macrophage polarization and restore the M1/M2 balance. Mechanistically, METTL14 overexpression mediated JAK2 mA RNA methylation and promoted the decay of JAK2 mRNA, leading to the inhibition of the JAK2/STAT3 signaling pathway. These findings suggest an important role of METTL14 in regulating adipose tissue dysfunction and metabolic inflammation caused by OSA. Modulating mA RNA methylation of the JAK2/STAT3 signaling pathway has therapeutic potential for OSA-related metabolic disorders and systemic inflammation.
Osteoblast-Derived Osteomodulin Suppresses Bone Loss in Osteoporosis by Inhibiting Osteoclastogenesis.
Jing M, Zhu X, Yang Y … +7 more , Hu X, Tan W, Liu X, Zhang Y, Wang X, Niu C, Huang Z
FASEB J · 2026 May · PMID 42186728 · Publisher ↗
Osteoporosis is a prevalent systemic skeletal disorder that leads to bone fragility and an elevated risk of fractures. Osteomodulin (OMD) is recognized for its essential role in bone morphogenetic protein 2 (BMP2)-driven...
Osteoporosis is a prevalent systemic skeletal disorder that leads to bone fragility and an elevated risk of fractures. Osteomodulin (OMD) is recognized for its essential role in bone morphogenetic protein 2 (BMP2)-driven osteogenic differentiation. However, its role in osteoporosis, has not been systematically investigated. Here, we carried out omics studies on osteoporotic data obtained from the NCBI database and showed that OMD is mainly expressed in osteoprogenitor cells and that OMD expression levels are down-regulated under bone loss conditions. OMD osteoblast-specific conditional knockout mice (OSTEOCALCIN-Cre (OC-Cre); Omd) were generated by CRISPR and an ovariectomy (OVX)-induced model of osteoporosis was constructed in mice. Micro-CT of OVX mice indicated that the trabecular bone volume fraction (BV/TV) was significantly decreased in OC-Cre; Omd mice. Tartrate resistant acid phosphatase (TRAP) staining showed an increase in the number of osteoclasts in the femurs of OC-Cre; Omd mice. TRAP and immunofluorescence staining indicated that OMD treatment inhibited osteoclast differentiation of bone marrow-derived macrophages (BMDMs) in vitro. RNA sequencing showed that OMD treatment significantly affected osteoclast differentiation signaling pathways, while western blot analysis revealed that OMD treatment decreased the phosphorylation of JNK, ERK, p38, AKT, and IκBα in BMDMs. Molecular docking analysis predicted that OMD binds to receptor activator of nuclear factor kappa beta ligand (RANKL), which was verified by co-immunoprecipitation. Further molecular docking simulations indicated that OMD shares overlapping binding regions on RANKL with osteoprotegerin and RANK. Together, our findings indicate that OMD deficiency exacerbates bone loss in osteoporosis. Furthermore, OMD may impede osteoclastic differentiation in BMDMs by binding to RANKL.
TET2-CHIP: From Mutation to Malady.
Jian H, Sun M, Xia X … +7 more , Su C, Su K, Xu J, Yuan Y, Li C, Yu M, Cheng X
FASEB J · 2026 May · PMID 42186714 · Publisher ↗
Somatic mutations in hematopoietic cells can drive clonal expansion without overt malignancy, a condition defined as clonal hematopoiesis of intermediate potential (CHIP). Among CHIP driver genes, TET2 is notable for its...
Somatic mutations in hematopoietic cells can drive clonal expansion without overt malignancy, a condition defined as clonal hematopoiesis of intermediate potential (CHIP). Among CHIP driver genes, TET2 is notable for its high prevalence and strong association with cardiovascular disease (CVD) and chronic inflammation. TET2 encodes a methylcytosine dioxygenase essential for epigenetic regulation, and its loss impairs hematopoietic stem cell differentiation while altering the functions of mature myeloid and lymphoid cells. Aging-related inflammation, along with lifestyle exposures, metabolic disorders, cancer therapy, and HIV infection, affects the emergence and expansion of TET2-mutant clones. Recently, evidence increasingly links TET2-CHIP to the incidence and prognosis of diverse CVDs. Emerging studies also suggest potential therapeutic strategies for TET2-CHIP-associated cardiovascular disease. This review summarizes current understanding of TET2 biology, mechanisms of TET2-CHIP development, and its cardiovascular implications.
Micro- and Nanoplastics in South and Southeast Asia: Lessons Learned and Future Directions.
Ali N
FASEB J · 2026 May · PMID 42186709 · Publisher ↗
Micro- and nanoplastics (MNPs) are becoming a significant public health concern, with growing evidence of widespread human exposure in South and Southeast Asia through food, drinking water, air, and occupational settings...
Micro- and nanoplastics (MNPs) are becoming a significant public health concern, with growing evidence of widespread human exposure in South and Southeast Asia through food, drinking water, air, and occupational settings. Nanoplastics, in particular, represent an under-recognized fraction with distinct exposure pathways and biological relevance. Although causal pathways are not fully established, the consistency of regional exposure patterns and emerging toxicological evidence warrant policy attention. In this region, rapid plastic production, high levels of mismanaged waste, large informal recycling sectors, and climate-exposed riverine and coastal systems create complex and overlapping exposure pathways. These conditions disproportionately affect vulnerable populations, including children, pregnant women, informal workers, and coastal communities. Key findings indicate that MNP exposure is widespread, poorly monitored, and inadequately addressed by policies that focus mainly on macroplastic waste management rather than health protection. Current regulatory frameworks rarely distinguish between microplastics and nanoplastics, even though their behavior, detection, and toxicity differ. This review identifies fragmented governance and weak integration across environmental regulation, food safety, occupational health, and public health systems as key policy gaps. Lessons from air pollution, lead, and other environmental hazards highlight the risks of delaying action. Priority policy directions include applying the precautionary principle, strengthening integrated surveillance and biomonitoring, regulating upstream plastic sources, and protecting high-risk populations. Ministries of Health should integrate MNP exposure into surveillance systems, occupational health frameworks, and maternal and child health programs.
Molecular Clocks in Translational Roadmap for Circadian-Based Therapeutics in Lung Diseases.
Panda K, Khasa R, Chinnapaiyan S … +3 more , Aggarwal S, Rahman I, Unwalla H
FASEB J · 2026 May · PMID 42186698 · Publisher ↗
The lung contains a robust peripheral circadian clock that regulates airway tone, epithelial barrier integrity, immune cell trafficking, and metabolic homeostasis through transcriptional-translational feedback loops invo...
The lung contains a robust peripheral circadian clock that regulates airway tone, epithelial barrier integrity, immune cell trafficking, and metabolic homeostasis through transcriptional-translational feedback loops involving BMAL1, CLOCK, PER, CRY, REV-ERBα, and RORα. Disruption of this molecular clock is increasingly recognized as a central pathogenic mechanism across pulmonary diseases. Inflammatory signaling, cigarette smoke, hyperoxia, infection, and developmental stress suppress core clock components, dampen clock-controlled gene rhythms, and drive persistent inflammation, impaired mucociliary clearance, oxidative injury, epithelial-mesenchymal transition, fibrosis, and tumor progression. Altered rhythmicity of BMAL1, REV-ERBα, PER2, and RORα has been reported in asthma, COPD, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, pneumonia, and lung cancer, correlating with characteristic diurnal fluctuations in symptoms and lung function. This narrative review integrates current evidence linking chronodisruption to pulmonary pathobiology and highlights emerging therapeutic strategies aimed at restoring circadian homeostasis. Small-molecule modulators of REV-ERBα, RORα, CRY, PER, CLOCK, and metabolic pathways (NAD-SIRT1 axis), in conjunction with chronotherapy-based timing of standard treatments, show potential to reestablish rhythmic gene expression and attenuate inflammation and tissue remodeling. The lung circadian clock is a central regulator of respiratory physiology and a promising therapeutic target in chronic lung disease. Strategies that restore rhythmicity, including clock-directed small molecules and time-optimized therapies, offer emerging opportunities to reduce inflammation, prevent maladaptive remodeling, and improve clinical outcomes.
Integrated Multi-Omics and Experimental Validation Reveal Dysregulation of the OXPHOS-NADPH-GSH Axis in Renal Fibrosis.
Wu D, Zhao J, Chang X … +5 more , Lei Y, Mu C, Yang D, Ye T, Xu S
FASEB J · 2026 May · PMID 42175955 · Publisher ↗
Chronic renal failure (CRF) is a growing global health burden, with renal fibrosis representing its key pathological feature. However, the metabolic mechanisms linking mitochondrial dysfunction to redox imbalance during...
Chronic renal failure (CRF) is a growing global health burden, with renal fibrosis representing its key pathological feature. However, the metabolic mechanisms linking mitochondrial dysfunction to redox imbalance during fibrogenesis remain incompletely understood. In this study, we investigated the relationship between mitochondrial oxidative phosphorylation (OXPHOS) disruption and alterations in cellular redox metabolism during CRF progression. Integrated proteomic and metabolomic analyses revealed remodeling of mitochondrial respiratory chain components together with reduced expression of NADPH-generating enzymes, including ME1, ME2, and IDH1. These changes were accompanied by decreased NADPH availability, imbalance of the glutathione redox system (GSH/GSSG), and suppression of NRF2-dependent antioxidant defenses, including HO-1 and GPX4. These alterations were associated with increased oxidative stress and extracellular matrix accumulation in fibrotic kidneys. In vitro experiments further showed that N-acetylcysteine (NAC) partially restored redox homeostasis, improved mitochondrial function, and attenuated TGF-β1-induced profibrotic responses in renal fibroblasts. In addition, the mitochondria-targeted antioxidant Mito-TEMPO reduced mitochondrial ROS accumulation and alleviated fibroblast activation. Collectively, these findings suggest that coordinated disruption of mitochondrial OXPHOS, NADPH metabolism, and glutathione-dependent antioxidant defense is associated with redox imbalance during renal fibrosis. Targeting mitochondrial redox metabolism may therefore represent a potential strategy for mitigating fibrotic progression in CRF.
Insulin Producing Cells Specific dilp2 Knockdown Induced T1D Model Reveals Circadian and Oxidative Stress Associated DEPs.
Kushwaha S, Kumar D, Kumar P … +5 more , Kumar P, Kumari S, Yadav N, Singaravel M, Srikrishna S
FASEB J · 2026 May · PMID 42175954 · Publisher ↗
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by impaired glucose homeostasis and persistent hyperglycemia. Drosophila has emerged as a valuable model to study conserved insulin signaling mechanisms;...
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by impaired glucose homeostasis and persistent hyperglycemia. Drosophila has emerged as a valuable model to study conserved insulin signaling mechanisms; proteomic insights into T1D-like conditions remain limited. Existing T1D models based on complete ablation of insulin-producing cells (IPCs) often exhibit severe developmental defects limiting their utility for dissecting disease-associated molecular and circadian mechanisms. Here, we report the establishment of an alternative Drosophila T1D model by targeting IPC-specific knockdown of dilp2, a homolog of human insulin, without IPC ablation. This novel model recapitulates key T1D-like features without affecting body size or weight, unlike other conventional models. Molecular analysis revealed elevation in phosphorylated Akt, reduced dfoxo and mTOR expression, and lifespan extension, suggesting a compensatory upregulation of dilp3 and dilp5. Our HRAMS-based proteomics study, for the first time, identifies five differentially expressed proteins (DEPs): Disc overgrown kinase (dco), Glutathione S-transferase 1 (GstS1), Turandot A (TotA), Turandot C (TotC), and Proteasome subunit beta type 6 (Prosβ6), validated by qRT-PCR. Downregulation of dco and GstS1 is associated with circadian arrhythmicity and elevated oxidative stress, respectively, whereas upregulation of TotA, TotC, and Prosβ6 reflects activation of stress responses and disruption of proteostasis under T1D-like conditions. Notably, circadian rhythm analysis exhibited hyperactivity and arrhythmic locomotor behavior in T1D flies. Collectively, these findings demonstrate dilp2 knockdown alone can induce T1D-like symptoms including multiple metabolic, circadian, and proteomic insights. The newly identified DEPs may serve as potential candidates for biomarker/therapeutic targets in T1D pathophysiology.
Temporal Association Between Diabetes and Depression and Their Impact on Cardiovascular Disease in Chinese Older Adults.
Huang M, Tian X
FASEB J · 2026 May · PMID 42175952 · Publisher ↗
Previous studies on the direction of the association between diabetes and depression were inconsistent, leaving a knowledge gap in understanding the temporal sequence of the association and its impact on the risk of card...
Previous studies on the direction of the association between diabetes and depression were inconsistent, leaving a knowledge gap in understanding the temporal sequence of the association and its impact on the risk of cardiovascular disease (CVD). This study aimed to examine the temporal relationship between diabetes and depression and their impact on the risk of CVD. We included 7124 participants aged ≥ 45 years with repeated measurement of glycated hemoglobin (HbA1c) and depression (measured by Center for Epidemiological Studies-Depression scale, CES-D) from the China Health and Retirement Longitudinal study. The cross-lagged panel and mediation analyses were performed to assess the temporal relationship between HbA1c and depression, and their impact on CVD. The adjusted cross-lagged path coefficient from baseline HbA1c to follow-up CES-D score (β, 0.181; 95% confidence interval [CI], 0.033-0.329; p = 0.0165) was significantly greater than the path coefficient from baseline CES-D to follow-up HbA1c (β, 0.001; 95% CI, -0.005 to 0.003; p = 0.6442) (p = 0.0160), indicating a unidirectional relationship between HbA1c and CES-D. Similar results were observed for the unidirectional relationship between baseline HbA1c and annual changes in CES-D (p = 0.0453). The annual changes in CES-D during the follow-up period significantly increased with higher quartiles of baseline HbA1c (p = 0.005 for trend). Additionally, 14.45% of total association between HbA1c and CVD was mediated through follow-up depression. Among Chinese middle-aged and elder adults, diabetes was associated with a subsequent increase in depression, and depression partially mediated the pathways from diabetes to incident CVD.
Different Functions of Mitofusin in Influencing the Migration and Invasion of BT20 via Regulating Metabolism and EMT.
Zhang P, Dong Q, Luo J … +7 more , He J, Guo X, Li M, Feng J, Long X, Zheng WV, Cui P
FASEB J · 2026 May · PMID 42175951 · Publisher ↗
Triple-negative breast cancer (TNBC) has a high rate of metastasis and recurrence, and lacks targeted and accurate treatment strategies. Mitochondrial metabolic reprogramming is a potential marker for cancer therapy, and...
Triple-negative breast cancer (TNBC) has a high rate of metastasis and recurrence, and lacks targeted and accurate treatment strategies. Mitochondrial metabolic reprogramming is a potential marker for cancer therapy, and mitochondrial metabolic changes mediated by mitochondrial dynamics have been used to inhibit the metastatic potential of various cancers. However, how the epithelial-mesenchymal transition (EMT) and metabolism mediated by the different homologous mitochondrial fusion proteins MFN1/2 affect breast cancer migration and invasion, and their compensatory effects have not been studied. Herein, we demonstrated that MFN1 knockdown significantly inhibited the mitochondrial membrane potential and enhanced the intracellular ATP content, proliferation, migration, invasion, and tumorigenic ability of BT20 by enhancing glycolysis. Disturbing MFN2 had a similar effect on the mitochondrial metabolic performance of BT20 as MFN1, but showed no significant effect on the proliferation, migration, and invasion of BT20. MFN1 knockdown promoted the migration and invasion of BT20 by inducing mitochondrial division and EMT. Furthermore, we discovered that MFN2 could, to a certain extent, reverse the effects of MFN1 knockdown on mitochondrial metabolism, proliferation, EMT, migration, and invasion efficiency in BT20 through the compensation experiments. Meanwhile, Mdivi-1 could reverse the EMT changes and cell morphology caused by MFN1 knockdown via inhibiting mitochondrial fission in BT20. 2DG could also reverse these changes by inhibiting glycolysis, and this process is mediated by enhancing AMPK, MAPK/ERK signaling, and inhibiting PI3K/Akt signaling. This study provides innovative ideas for the targeted regulation of mitochondrial fusion in TNBC therapy.
Targeting the Skeletal Muscle Microenvironment: A Novel Therapeutic Strategy for Skeletal Muscle Aging.
Yu Y, He Y, Wang Y … +4 more , Wu C, Zhou R, Chen F, Ma W
FASEB J · 2026 May · PMID 42175950 · Publisher ↗
Sarcopenia, a hallmark of skeletal muscle aging, is a significant public health concern that substantially compromises the quality of life in the elderly. While conventional research has predominantly focused on intrinsi...
Sarcopenia, a hallmark of skeletal muscle aging, is a significant public health concern that substantially compromises the quality of life in the elderly. While conventional research has predominantly focused on intrinsic pathological alterations within muscle fibers, it has often overlooked the diverse cell-cell and interorgan communications mediated by nonmuscle cells in the skeletal muscle microenvironment. This microenvironment, comprising the extracellular matrix, multiple cellular components, secreted factors, and metabolites, plays a crucial role in regulating muscle homeostasis and regeneration, serving as a key driver of skeletal muscle aging. As the microenvironment undergoes profound remodeling with advancing age, this review systematically examines novel intervention strategies targeting it. By aiming to achieve coordinated multipathway remodeling of this niche, these approaches offer a fresh theoretical foundation and novel clinical avenues for delaying or reversing sarcopenia. Future research should prioritize elucidating these microenvironmental regulatory mechanisms, refining personalized intervention protocols, and rigorously validating translational applications.
Breaking the Heat Tolerance Response: The Crucial Role of MFAP4 in Combating Heat-Induced Cardiac Injury.
Fan L, Song M, Zhang Q … +6 more , Guo Z, Wang J, Chen X, Hu C, Lu J, Xi Z
FASEB J · 2026 May · PMID 42175942 · Publisher ↗
Heat exposure increases cardiac workload and impairs thermoregulation, leading to cardiac injury and heatstroke (HS). The involvement of Microfibrillar-associated protein 4 (MFAP4) in HS remains unclear. This study aims...
Heat exposure increases cardiac workload and impairs thermoregulation, leading to cardiac injury and heatstroke (HS). The involvement of Microfibrillar-associated protein 4 (MFAP4) in HS remains unclear. This study aims to investigate the role and mechanisms of MFAP4 in heat-induced damage. Whole body MFAP4-knockout (MFAP4-KO) mice and MFAP4-overexpressing cells were generated. Physiological and pathological responses were assessed in vivo/vitro experiments. An HS model exposed mice to (39.5 ± 0.5)°C/(55 ± 5)% humidity; and cell to 44°C with 5% CO₂ for 2 h. Transcriptomic analysis was performed to investigate the mechanisms underlying myocardial injury. MFAP4-KO mice exhibited accelerated core temperature rise, recovery of core temperature to 36.5°C was delayed, and reduced survival during HS (p < 0.05). HS induced left ventricular dilation (elevated LVIDd/LVIDs), systolic dysfunction (reduced EF/FS), myocardial injury (increased serum cTnT/cTnI), and fibrosis, all of which were exacerbated by MFAP4 deficiency. HS significantly elevated MFAP4 levels in serum and aorta, while MFAP4 deficiency mice hearts showed compensatory activation of the HSF1/HSP70 signaling pathway. MFAP4 overexpression increased cellular resistance to HS. Transcriptomic analysis revealed a 79% reduction in heat-responsive genes, and reversed 98 genes, confirming MFAP4 as a central cardiac protective role regulator of HS. MFAP4 deficiency also influenced Zbp1, Ccl12, and Cxcl10 expression through thermogenesis, and vascular smooth muscle contraction pathways. MFAP4 is a critical mediator of cardiovascular protection during acute HS. Its deficiency leads to thermoregulatory failure, and disrupts myocardial proteostasis by impairing the HSF1/HSP70 signaling axis, thereby exacerbating cardiac injury. MFAP4 likely increases myocardial resilience by regulating a ZBP1/CXCL10-centered network, thereby exerting a cardioprotective effect.
CAMK1 Suppresses Anoikis Resistance and Liver Metastasis in Colorectal Cancer.
Feng Q, Hao Y, Cheng Y … +11 more , Liu D, Jin M, Li T, Li C, Li Q, Sun L, Gao Y, Mu J, Ji F, Liu X, Wang D
FASEB J · 2026 May · PMID 42175534 · Publisher ↗
Metastasis represents a major challenge in the treatment of clinical colorectal cancer (CRC), and anoikis resistance enables cancer cell dissemination. This study identifies Calcium/calmodulin-dependent protein kinase I...
Metastasis represents a major challenge in the treatment of clinical colorectal cancer (CRC), and anoikis resistance enables cancer cell dissemination. This study identifies Calcium/calmodulin-dependent protein kinase I (CAMK1) as a crucial regulator of anoikis in CRC progression. We analyzed CAMK1 expression in CRC tissues and its correlation with patient prognosis. In vitro, CAMK1 was overexpressed in CRC cell lines to assess its effects on proliferation, migration, invasion, and anoikis resistance. In vivo, mouse models were established to evaluate the impact of CAMK1 overexpression on tumor growth and liver metastasis. Mechanistically, we examined the interaction between CAMK1 and Phosphoinositide 3-kinase (PI3K), as well as the phosphorylation of PI3K and the activation of the downstream Protein kinase B (AKT) pathway. Mitochondrial function indicators were simultaneously measured: membrane potential, reactive oxygen species (ROS) production, and apoptosis markers, including the Bax/Bcl-2 ratio and Caspase-3 activation. Rescue experiments were conducted using the PI3K activator 740 Y-P. CAMK1 expression was significantly downregulated in CRC tissues, and low CAMK1 levels correlated with poor patient prognosis. In vitro, overexpression of CAMK1 significantly inhibited the malignant phenotypes of CRC cells and sensitized them to anoikis. Consistently, CAMK1 overexpression suppressed tumor growth and hepatic metastasis in mouse models. Mechanistically, CAMK1 interacted with PI3K, inhibiting its phosphorylation and subsequent AKT pathway activation. This inhibition induced mitochondrial dysfunction, characterized by depolarization of the mitochondrial membrane potential and increased ROS production, and promoted apoptosis, as evidenced by an elevated Bax/Bcl-2 ratio and Caspase-3 activation. Notably, the PI3K activator 740 Y-P effectively reversed the pro-anoikis effects and mitochondrial alterations induced by CAMK1, confirming the pivotal role of the PI3K/AKT pathway in this regulation. CAMK1 functions as a novel tumor suppressor in CRC. It constrains anoikis resistance and metastasis by inhibiting the PI3K/AKT signaling pathway, thereby disrupting mitochondrial function. These findings highlight the dual potential of CAMK1 as both a prognostic biomarker and therapeutic target in colorectal cancer.
HIF-1α/HMOX1-Mediated Ferroptosis in Macrophages Exacerbates Malaria Progression.
Liang G, Li J, Xie X … +12 more , Yuan H, Xiao W, Chen M, Lu K, Xu L, Pan L, Wei H, Li L, Zhao S, Xie H, Pan X, Huang J
FASEB J · 2026 May · PMID 42172503 · Publisher ↗
The spleen orchestrates anti-malarial immunity, with its macrophages phagocytizing Plasmodium-infected blood cells (iRBCs). While regulated cell death (RCD) has been extensively studied in various diseases, the relations...
The spleen orchestrates anti-malarial immunity, with its macrophages phagocytizing Plasmodium-infected blood cells (iRBCs). While regulated cell death (RCD) has been extensively studied in various diseases, the relationship between regulatory cell death of splenic macrophages and the progression of malaria infection remains unexplored. In this study, we identify that Plasmodium infection triggers ferroptosis in splenic macrophages characterized by aberrant HMOX1 upregulation concomitant with HIF-1α downregulation. Mechanistically, the loss of HIF-1α signaling fails to restrain HMOX1 expression, leading to Fe overload. Fer-1 inhibits ferroptosis in iRBC-exposed macrophages in vitro. P. yoelii-infected mice show elevated ferroptosis biomarkers in splenic macrophages, reversible by Fer-1 treatment. Additionally, compared to GPX4 infected mice, the conditional knockout infected mice (GPX4 Lyz2Cre) display worsened health conditions and more severe parasitemia. Moreover, identical ferroptosis signature is detected in monocytes from malaria patient PBMCs, confirming cross-species conservation. In conclusion, these findings suggest that Plasmodium yoelii NSM infection triggers ferroptosis in splenic macrophages, which exacerbates malaria progression. Targeting the HIF-1α/HMOX1 axis to modulate macrophage ferroptosis alleviates the progression of Plasmodium infection, providing crucial mechanistic insights that warrant cautious exploration for host-directed interventions.
Modular Organization of Rba50 Reveals Distinct Domains for RNAPII Assembly and Interaction Network Formation.
Xie D, Wang L, Sun X … +5 more , Yan Y, Li P, Gao M, Quintana DG, Zeng F
FASEB J · 2026 May · PMID 42172452 · Publisher ↗
RNA polymerase II (RNAPII) is a conserved 12-subunit enzyme essential for eukaryotic transcription. Although the structure and biological functions of RNAPII are well-defined, the mechanisms by which its subunits are ass...
RNA polymerase II (RNAPII) is a conserved 12-subunit enzyme essential for eukaryotic transcription. Although the structure and biological functions of RNAPII are well-defined, the mechanisms by which its subunits are assembled into a functional complex remain only partially understood. Several RNAPII assembly factors have been identified, but the molecular principles by which they cooperate during polymerase biogenesis remain unclear. Rba50 is an essential, conserved RNAPII assembly factor implicated in multiple stages of polymerase biogenesis, yet its mode of action remains unknown. Here, we combine structural prediction, targeted interaction assays, and functional analyses to reveal a modular organization of Rba50 with separable activities. Rba50 comprises two functionally distinct but cooperative regions: a structured C-terminal module that provides RNAPII assembly-associated activity and an intrinsically disordered N-terminal module that functions as a multivalent interaction hub. We map a direct interaction between the assembly factor Npa3 and the first N-terminal disordered segment, residues 1-89, and show that the N-terminal module expands the Rba50 interaction network. Functional assays indicate that the C-terminal region rescues specific rba50-3 phenotypes and supports proliferative recovery under permissive plasmid-shuffle conditions, whereas robust Rba50 function also requires determinants outside the C-terminal region. We further identify a CRM1-dependent leucine-rich nuclear export signal within residues 239-249 that limits nuclear accumulation of Rba50 at steady state. Together, our results support a modular architecture in which distinct functional elements within Rba50 contribute to RNAPII biogenesis, interaction-network formation, and nucleocytoplasmic distribution.
Aortic Segments-Depending Hypertensive Remodeling Is Driven by Mitochondrial Fusion Dysfunction.
Richard A, Vicente AB, Gourhand C … +12 more , Ducroix A, Robert P, Toutain B, Grimaud L, Vessières E, Toutain-Barbelivien A, Lenaers G, de la Barca JC, Fouquet O, Henrion D, Fassot C, Loufrani L
FASEB J · 2026 May · PMID 42172445 · Publisher ↗
OPA1 haploinsufficiency exacerbates severe hypertension-induced aortic remodeling in a segment-specific manner, revealing differential vulnerability between the suprarenal abdominal aorta (SRAA) and the descending thorac...
OPA1 haploinsufficiency exacerbates severe hypertension-induced aortic remodeling in a segment-specific manner, revealing differential vulnerability between the suprarenal abdominal aorta (SRAA) and the descending thoracic aorta (DTA). In the SRAA, hypertension activates mitochondrial fission pathways (DRP1, FIS1) and mitophagy markers (PINK1, PARKIN), without triggering full autophagic flux (LC3B, p62). Respiratory chain complexes I and IV are upregulated in hypertensive Opa1 mice across both segments, reflecting a compensatory mitochondrial stress response. Apoptotic analysis shows increased TUNEL staining in both regions, while caspase-3 and 9 activation is restricted to the SRAA. Inflammatory profiling reveals a predominance of M1 macrophages, specifically in the SRAA. Morphometric assessment highlights major impacts in SRAA, such as luminal dilation and adventitial thickening, confirmed by in vivo representative ultrasound images. These findings underscore the pivotal role of OPA1 in mitochondrial homeostasis and reveal, for the first time, a region-specific protective function of OPA1 within the aortic wall under severe hypertensive stress. This differential impact, according to aortic segment anatomy and physiology, opens new avenues for hypertension and pathological aorta remodeling therapies.
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