FASEB Journal[JOURNAL]
Sun
200 papers
Hirsutine Ameliorates High-Fat Diet-Induced Cardiomyopathy Through Promoting LRPPRC-Regulated Mitophagy via the PINK1/Parkin Axis in Mice.
Ding L, Ma J, Fang Z … +10 more , Wang J, Ye Z, Lai J, Liao Y, Chen S, Chen Y, Fan J, Fan X, Gong Y, Jin P
FASEB J · 2026 Jun · PMID 42290393 · Publisher ↗
Hirsutine, a potent drug-like indole alkaloid extracted from Uncaria rhynchophylla, exhibits several biological activities, including cardioprotective effects. However, the underlying regulatory mechanisms remain unclear...
Hirsutine, a potent drug-like indole alkaloid extracted from Uncaria rhynchophylla, exhibits several biological activities, including cardioprotective effects. However, the underlying regulatory mechanisms remain unclear. Herein, we aimed to examine the therapeutic effects of hirsutine on obesity-related cardiomyopathy and investigate the potential mechanism underlying these effects. An obesity cardiomyopathy mouse model was developed by subjecting mice to a high-fat diet (HFD) for 16 consecutive weeks, followed by an 8-week hirsutine treatment. H9c2 cardiomyocytes treated with palmitate were utilized as an in vitro model. Invasive hemodynamic parameters and left ventricular hypertrophy indices were assessed, and the expression of related signaling molecules was analyzed using western blotting, mass spectrometry, molecular docking, RNA sequencing, immunoprecipitation, histological analysis, and transmission electron microscopy, respectively. Hirsutine significantly alleviated HFD-induced cardiomyopathy in the mouse model. Notably, the therapeutic effect of hirsutine was reversed in Midivi-1-treated mice, indicating that the cardioprotective role of hirsutine is dependent on mitochondrial fission-mediated mitophagy and Parkin. Mechanically, hirsutine maintained Parkin protein stability, and the C-terminal region of 1103-1394 amino acids of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) functions as a binding motif interacting with Parkin. LRPPRC overexpression significantly enhanced Parkin protein stability, which was attenuated by deletion of the 1103-1394 amino acids of LRPPRC (LRPPRC). Collectively, these findings demonstrate that hirsutine ameliorates HFD-induced cardiomyopathy by promoting Parkin protein stability through its interaction with 1103-1394 amino acids of LRPPRC. Therefore, targeting LRPPRC may represent a promising therapeutic strategy underlying the protective effects of hirsutine in HFD-induced cardiomyopathy.
Correction to "Inhibition of α1-Adrenoceptor Reduces TGF-β1-Induced Epithelial-To-Mesenchymal Transition and Attenuates UUO-Induced Renal Fibrosis in Mice".
FASEB J · 2026 Jun · PMID 42290238 · Publisher ↗
Abstract loading — click title to view on PubMed.
Exercise-Induced Irisin Antagonizes TGFBR2 to Attenuate Islet Fibrosis and Improve Glucose Homeostasis in Type 2 Diabetes.
Wang Q, Wang X, Cai Z … +5 more , Carvalho V, Wang H, Chen Y, Sun Z, Qiu S
FASEB J · 2026 Jun · PMID 42287608 · Publisher ↗
This study examined the effects of exercise on islet fibrosis in mice with type 2 diabetes and investigated the role of irisin in the regulation of islet stellate cell (ISC) activation. Following the 16-week moderate-int...
This study examined the effects of exercise on islet fibrosis in mice with type 2 diabetes and investigated the role of irisin in the regulation of islet stellate cell (ISC) activation. Following the 16-week moderate-intensity exercise intervention, db/db mice showed reduced body weight and improved glucose tolerance and insulin sensitivity. This exercise intervention also decreased collagen-I (Col-I), fibronectin (FN), and α-smooth muscle actin (α-SMA); reduced islet fibrosis area (assessed by Masson staining); and lowered the numbers of α-SMA-positive ISCs in the pancreas. Serum irisin was increased after a single bout of moderate-intensity exercise but decreased following the 16-week exercise intervention. In vitro experiments showed that irisin suppressed ISC activation by delaying lipid droplet loss, inhibiting migration, and reducing expression of α-SMA, Col-I, and FN. Irisin also attenuated advanced glycation end products-or transforming growth factor-β (TGF-β)-induced ISC activation and extracellular matrix production and competitively bound to TGF-β receptor 2 (TGFBR2), inhibiting TGF-β/Smad pathway phosphorylation. These findings suggest that exercise may help to alleviate diabetes-related islet fibrosis, in part by suppressing ISC activation via irisin-mediated inhibition of TGF-β/Smad signaling.
Don't Sweat It: Cannabinoid CB1 Receptors Reduce Sweating in a Mouse Model.
Murataeva N, Youkilis J, Rao Y … +1 more , Straiker A
FASEB J · 2026 Jun · PMID 42287607 · Full text
Numerous exocrine glands play key physiological roles in the body that include tearing, salivation, and lactation, as well as the control of body temperature via sweating. Malfunction of sweat glands can be deeply proble...
Numerous exocrine glands play key physiological roles in the body that include tearing, salivation, and lactation, as well as the control of body temperature via sweating. Malfunction of sweat glands can be deeply problematic or-in the case of anhidrosis-life-threatening. The prevalence of sweating disorders is high, affecting millions. The few available therapies are generally of limited effectiveness. Several lines of evidence point to regulation of sweating by the cannabinoid signaling system, an arrangement that would mirror cannabinoid regulation of tearing and salivation. Mice sweat in their paws via glands that closely resemble human eccrine sweat glands, including regulation by muscarinic signaling and by temperature. We applied a galvanic skin response-based assay to investigate cannabinoid regulation of sweating in awake, unanesthetized mice. The muscarinic agonist pilocarpine increased conductance while the antagonist glycopyrrolate reduced conductance, validating the model as a measure of sweating. The cannabinoid receptor agonist CP55940 substantially reduced conductance in wild-type and CB2 but not CB1 receptor knockout mice. The phytocannabinoid tetrahydrocannabinol (THC) also reduced conductance, while the non-psychoactive cannabidiol (CBD) did not. Using immunohistochemistry, we detected CB1 receptors in periglandular cholinergic axons, the anandamide-synthesizing enzyme NAPE-PLD in myoepithelial cells, and the anandamide metabolizing enzyme FAAH in acinar cells. This indicates that a local CB1/anandamide-based circuit is present in mouse walking pads. In summary, we employed a novel galvanic skin response-based assay to determine that cannabinoid CB1 receptors reduce sweating in a mouse model. This may point to a previously unappreciated effect on sweating in cannabis users.
S100A4 Orchestrates Fibroblast Fate to Drive Fibrotic Remodeling.
Li S, Cai B, Zhang X … +4 more , Cai G, Zhou Y, Wagener BM, Ding Q
FASEB J · 2026 Jun · PMID 42287596 · Full text
Fibroblast survival and dysregulated activation drive fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). During physiological wound repair, fibroblasts are transiently activated to restore tissue integrity...
Fibroblast survival and dysregulated activation drive fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). During physiological wound repair, fibroblasts are transiently activated to restore tissue integrity and are subsequently cleared by programmed cell death. In fibrotic disease, however, fibroblasts evade apoptosis and persist in a pathologically activated state. Although S100A4 has been implicated in fibrotic lung disease, the mechanisms by which S100A4 governs fibroblast fate and sustains profibrotic behavior remain unclear. Here, we identify S100A4 as a key regulator of apoptosis-resistant, profibrotically activated fibroblasts through engagement of extracellular signal-regulated kinase (ERK) signaling. In primary murine lung fibroblasts, S100A4 activates ERK, resulting in a coordinated program of fibroblast activation, including increased migration, extracellular matrix (ECM) contractility, stress fiber formation, and alpha-smooth muscle actin (α-SMA) induction. Functionally, S100A4 confers resistance to apoptosis induced by pro-apoptotic and oxidative stress stimuli, as evidenced by reduced cleaved caspase-3 and preserved cell viability. Pharmacological blockade of ERK signaling attenuates these responses, supporting ERK as an important downstream mediator of S100A4-driven fibroblast activation and survival programs. Extending these findings to disease-relevant contexts, bleomycin (BLM)-induced lung injury in mice induces robust fibrotic remodeling, excessive collagen deposition, and transcriptional upregulation of S100A4. Consistently, primary lung fibroblasts from IPF patients exhibit elevated S100A4 expression, enhanced ERK activation, and increased α-SMA expression, demonstrating conservation of this signaling axis across experimental models and human disease. Importantly, siRNA-mediated knockdown of S100A4 in IPF fibroblasts suppresses ERK activation and attenuates expression of key profibrotic genes, indicating that S100A4 contributes to maintaining the fibrotic program in IPF fibroblasts. Collectively, these findings define a mechanistic link between S100A4-mediated fibroblast survival and activation that drives pathological matrix remodeling and identify S100A4 and ERK as potential therapeutic targets in pulmonary fibrosis.
circTMEM230 Sponges miR-223-3p to Promote Endplate Chondrocyte Extracellular Matrix Synthesis and Attenuate Tension-Induced Disc Degeneration.
Zheng Q, Yang J, Li XX … +4 more , Shao S, Wang CD, Wang QW, Sun LY
FASEB J · 2026 Jun · PMID 42287310 · Publisher ↗
Circular RNAs (circRNAs) are important regulators of signaling pathways involved in intervertebral disc degeneration (IVDD). This study investigated the role and underlying mechanism of circTMEM230 in the degeneration of...
Circular RNAs (circRNAs) are important regulators of signaling pathways involved in intervertebral disc degeneration (IVDD). This study investigated the role and underlying mechanism of circTMEM230 in the degeneration of endplate chondrocytes. We observed that circTMEM230 expression was significantly downregulated in chondrocytes subjected to intermittent cyclic mechanical tension (ICMT). Functional assays demonstrated that overexpression of circTMEM230 enhanced the expression of extracellular matrix (ECM)-related genes through modulation of the miR-223-3p/FOXO3/SOX9 signaling axis. Specifically, circTMEM230 acted as a molecular sponge for miR-223-3p, thereby upregulating FOXO3, which subsequently promoted SOX9 transcription. In vivo experiments further confirmed that circTMEM230 mitigated IVDD progression and regulated the expression of miR-223-3p, FOXO3, and SOX9. Additionally, expression levels of circTMEM230, miR-223-3p, FOXO3, and SOX9 were found to be correlated in endplate cartilage tissue samples from IVDD patients. These findings suggest that circTMEM230 exerts a protective role in IVDD and may serve as a promising therapeutic target for further investigation.
Mesenchymal Stem Cells Therapy for Intrauterine Adhesions and Endometriosis: Potential, Mechanisms, and Future Directions.
Liu SH, He SY, Ji BQ … +3 more , Zhang XC, Li JY, Liu QW
FASEB J · 2026 Jun · PMID 42287087 · Publisher ↗
Intrauterine adhesions (IUA) and endometriosis are debilitating gynecological disorders that impair endometrial function and fertility. IUA, typically caused by iatrogenic trauma to the basal endometrium, leads to fibros...
Intrauterine adhesions (IUA) and endometriosis are debilitating gynecological disorders that impair endometrial function and fertility. IUA, typically caused by iatrogenic trauma to the basal endometrium, leads to fibrosis and infertility, whereas endometriosis, characterized by ectopic endometrial growth, induces chronic inflammation, pain, and subfertility. Current treatments, such as surgical adhesiolysis for IUA and hormonal suppression for endometriosis, frequently fail to address underlying pathological mechanisms, including aberrant fibrosis, inflammatory cascades, and impaired tissue regeneration. Recently, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach. Their therapeutic benefits are mediated primarily through paracrine actions, which modulate immune responses, promote tissue repair, and attenuate inflammation and fibrosis. Recent studies have further highlighted the potential of MSC-derived exosomes (MSC-Exos) as a cell-free alternative. In this review, we comprehensively summarize current evidence from animal models and clinical studies on the application of MSCs and MSC-Exos in treating IUA and endometriosis, focusing on their therapeutic potential, mechanisms of action, and future directions. We also discuss remaining challenges and promising strategies to overcome them, thereby positioning MSC-based therapies as transformative options for endometrial restoration and disease management.
Wound Healing and Angiogenic Profiling of Dermal Endothelial Cells Isolated From People With Type 2 Diabetes.
Shadiow J, Mazo CE, Varshney P … +12 more , Kim JJ, Ahn A, Chong SH, Lutz CA, Holmes CM, Munson ME, Schmidt BM, Goonewardena SN, Minshall RD, Solomon TPJ, Ludlow AT, Haus JM
FASEB J · 2026 Jun · PMID 42284134 · Full text
Impaired wound healing in type 2 diabetes (T2D) is associated with microvascular dysfunction and remains a significant clinical challenge. We aimed to determine whether primary human dermal microvascular endothelial cell...
Impaired wound healing in type 2 diabetes (T2D) is associated with microvascular dysfunction and remains a significant clinical challenge. We aimed to determine whether primary human dermal microvascular endothelial cells (HDMVECs) from individuals with T2D exhibit abnormal cellular functions, and whether exposure to T2D serum impacts healthy endothelial function. In Experiment 1, T2D-HDMVECs displayed paradoxically higher migratory and angiogenic capacities than their healthy counterparts, despite markedly reduced eNOS expression and disrupted endothelial-identity gene expression. In Experiments 2 and 3, healthy HDMVECs showed decreased tube formation, nitric oxide production, and Notch/angiogenesis-related gene expression after exposure to both healthy and T2D serum, suggesting the presence of serum-derived factors that suppress these pathways. However, T2D-HDMVECs remained largely unresponsive to these serum-driven effects, reinforcing an intrinsic reprogramming of T2D endothelial cells. Additional analyses revealed selective alterations in redox and angiogenic signaling pathways (e.g., NOX4, FLT1), whereas canonical regulators such as VEGFA and PFKB3 were not affected by serum exposure. Overall, our data reveal a complex interplay between cell-autonomous alterations and extrinsic signals in diabetic endothelial dysfunction. Therapeutic strategies targeting both intrinsic cellular programs (e.g., eNOS, Notch signaling) and the circulating milieu may represent promising avenues for enhancing wound repair in patients with T2D.
Dietary Divergence Along an Altitudinal Gradient Is Associated With Liver Transcriptomic and Metabolic Remodeling in a Small Mammal.
Yao B, Zhang Y, Chen X … +4 more , Wang Y, Tan Z, Chen H, Qu J
FASEB J · 2026 Jun · PMID 42284131 · Publisher ↗
Although physiological adaptations to high altitude are well-studied, the synergistic mechanisms linking foraging strategies to internal metabolism remain unclear. To investigate how dietary shifts are associated with mo...
Although physiological adaptations to high altitude are well-studied, the synergistic mechanisms linking foraging strategies to internal metabolism remain unclear. To investigate how dietary shifts are associated with molecular variation in plateau pikas (Ochotona curzoniae) along an altitudinal gradient, we integrated dietary analysis with liver transcriptomics and metabolomics. Results revealed a significant dietary differentiation in plateau pikas along the altitudinal gradient, shifting from a selective foraging strategy on diverse forbs at low altitudes to a tolerance foraging strategy centered on hardy sedges (Carex) and toxic locoweeds (Oxytropis) at high altitudes. Dietary differentiation along the altitudinal gradient was associated with coordinated changes in liver metabolism: low-altitude populations were enriched in metabolites related to biotic stress responses, whereas high-altitude populations showed increased accumulation of antioxidant compounds consistent with adaptation to intense abiotic stress. Transcriptomic analysis unveiled the molecular basis for this adaptation: the livers of high-altitude pikas exhibited significant upregulation of genes related to xenobiotic detoxification and energy metabolism regulation; in contrast, low-altitude populations upregulated pathways associated with cell growth and immune response. This study reveals a tightly coupled diet-gene-metabolism axis in plateau pikas. The shift in foraging strategy from selective to tolerance is a key driver of the functional shift in liver metabolism, redirecting the physiological focus from coping with biotic stress at low altitudes to counteracting abiotic stress at high altitudes. Our study highlights the importance of integrating ecological and molecular data to better understand how environmental gradients shape organismal physiology in natural populations.
Trichinella spiralis Serine Proteinase Disrupted Intestinal Epithelial Integrity via Binding to RACK1 and Activating ERK1/2 Pathway in Mice.
Wu JY, Zhang XZ, Zhang Y … +6 more , Zhang R, Zhang X, Liu RD, Long SR, Wang ZQ, Cui J
FASEB J · 2026 Jun · PMID 42284113 · Publisher ↗
Previous studies showed that a T. spiralis serine proteinase (TsSPc) was identified in intestinal infective larvae (IIL) surface and excretory-secretory (ES) proteins. The in vitro experiments revealed that rTsSPc bound...
Previous studies showed that a T. spiralis serine proteinase (TsSPc) was identified in intestinal infective larvae (IIL) surface and excretory-secretory (ES) proteins. The in vitro experiments revealed that rTsSPc bound to intestinal epithelial cells and promoted larval invasion, but the in vivo role of rTsSPc in T. spiralis infection remains unclear. The purpose of this study was to investigate the TsSPc's function and mechanism in T. spiralis infection in mice. Immunofluorescence assay (IFA), qPCR, and Western blotting showed that rTsSPc specifically bound and co-localized with RACK1 receptor in intestinal mucosal epithelium, activated the ERK1/2 pathway, decreased the expression of the tight junctions (E-cad, Occludin, and Claudin-1), increased intestinal permeability, impaired intestinal epithelial integrity and barrier function, thereby promoted T. spiralis invasion of intestinal mucosa. The H&E and PAS staining showed that rTsSPc also caused intestinal mucosal inflammation reactions; the number and size of goblet cells in the rTsSPc group were distinctly increased, and the expression levels of inflammatory cytokines (TNF-α, IL-1β, TGF-β, and IL-10) and mucins (Muc2 and Muc5ac) were significantly elevated. These findings further verified that the in vivo binding of TsSPc to RACK1 disrupted gut epithelial integrity and mediated T. spiralis invasion of intestinal mucosa, and TsSPc may be regarded as a potential vaccine target to block T. spiralis infection.
Urolithin C Exerts Anti-Endometrial Cancer Effects by Inducing Autophagy Through Specific Stimulation of ATF3.
Hu R, Liu C, Dong X … +12 more , Du H, Bi R, Zhang Y, Wang X, Liu X, Chen W, Wang F, Cui B, Dong H, Wang Y, Du J, Liu Z
FASEB J · 2026 Jun · PMID 42284106 · Publisher ↗
Urolithin C (UC), a natural compound derived from the metabolism of ellagitannins by gut microbiota, exhibits diverse pharmacological and biological activities. However, its therapeutic potential and underlying mechanism...
Urolithin C (UC), a natural compound derived from the metabolism of ellagitannins by gut microbiota, exhibits diverse pharmacological and biological activities. However, its therapeutic potential and underlying mechanisms in endometrial cancer (EC) remain unclear. Functional assays were used to determine the effects of UC on the viability, proliferation, cell cycle, apoptosis, migration, and autophagy in EC cells. RNA sequencing was used to investigate the effect of UC on total gene expression in EC cells. The expression level of activating transcription factor 3 (ATF3) was evaluated using western blotting, real-time PCR, and immunofluorescence staining. Organoids and a mouse model of EC were used to analyze the anti-tumor effects of UC. UC significantly inhibited the malignant behavior of EC cells. High-throughput transcriptome sequencing revealed a close association between autophagy and UC treatment, and identified ATF3 as a key downstream factor. UC treatment increased the expression of ATF3, which was primarily localized to the nucleus. Elevated ATF3 levels positively correlated with the survival of patients with EC. ATF3 knockdown rescued the effects of UC on cell viability, migration, and autophagy. Furthermore, EC organoid and in vivo experiments showed that UC markedly reduced organoid viability and EC tumor growth. UC exerts anti-EC activity by promoting ATF3 expression, thereby inhibiting the malignant behavior of EC cells and promoting autophagic cell death.
LAT1 Promotes Immunosuppression in Cervical Cancer by Interacting With TRIM67 to Facilitate IRF3 Ubiquitination and Degradation.
Pang H, Zhu S, Lu Q … +1 more , Zheng W
FASEB J · 2026 Jun · PMID 42284096 · Publisher ↗
Cervical cancer (CC) is characterized by tumor immune escape, which underlies suboptimal therapy responses and an increased recurrence risk. Despite the established role of LAT1 in cancer progression, its regulatory mech...
Cervical cancer (CC) is characterized by tumor immune escape, which underlies suboptimal therapy responses and an increased recurrence risk. Despite the established role of LAT1 in cancer progression, its regulatory mechanism in the CC immune microenvironment remains elusive. LAT1 expression in cervical squamous cell carcinoma and its correlation with CD8 T cell infiltration were assessed through the bioinformatic approach. LAT1 mRNA and protein expression were examined by qRT-PCR and Western blot, respectively. In a co-culture system with CC cells, CD8 T cell antitumor activity was measured by lactate dehydrogenase release, ELISA, CCK-8, colony formation, and flow cytometry. The LAT1/TRIM67 interaction was identified through bioinformatics and validated by Co-IP and immunofluorescence. Potential ubiquitination substrates of TRIM67 were screened through bioinformatics. CHX chase assays combined with ubiquitination analysis were employed to verify the IRF3 degradation pathway. Finally, in vivo functional validation was conducted in a mouse xenograft model. LAT1 was overexpressed in CC tissues and cell lines. LAT1 expression negatively correlated with CD8 T cell infiltration. LAT1 knockdown enhanced CD8 T cell antitumor activity. Mechanistically, LAT1 suppressed CD8 T cell antitumor function in CC by interacting with TRIM67 to promote ubiquitination and degradation of IRF3. LAT1 recruits TRIM67 to mediate IRF3 ubiquitination and degradation, ultimately suppressing CD8 T cell function and promoting immune escape. These findings provide a theoretical basis for targeting the LAT1/TRIM67 axis to enhance immunotherapy in CC.
SREBPs in Metabolic Reprogramming and Disease: Mechanisms and Therapeutic Potential.
Zou X, Li Y, Yang M … +4 more , Liu L, Wu R, Cui G, Dai J
FASEB J · 2026 Jun · PMID 42281411 · Publisher ↗
Sterol regulatory element-binding proteins (SREBPs) are key transcription factors belonging to the basic helix-loop-helix leucine zipper (bHLH-Zip) family. They play central roles in coordinating cellular lipid metabolic...
Sterol regulatory element-binding proteins (SREBPs) are key transcription factors belonging to the basic helix-loop-helix leucine zipper (bHLH-Zip) family. They play central roles in coordinating cellular lipid metabolic signaling and maintaining metabolic homeostasis. This review systematically summarizes the origin, classification, structural characteristics, and activation mechanisms of SREBPs mediated by the INSIG-SCAP-SREBP complex. Building on this, we further outline the lipid metabolic programs regulated by SREBPs, with a focus on their roles in de novo lipogenesis, triglyceride accumulation, cholesterol metabolism, and membrane remodeling. In addition, we provide a cross-disease overview of SREBP-driven metabolic reprogramming, highlighting its involvement in inflammation amplification, immune metabolic imbalance, disruption of cellular homeostasis, and malignant progression. Based on current advances, we also summarize emerging small-molecule modulators targeting SREBP signaling and their potential therapeutic value. Furthermore, we discuss key challenges in current research, including functional heterogeneity, context-dependent regulation, organismal and cell-type specificity, as well as barriers to clinical translation. Overall, SREBPs are not only central regulators of lipid metabolism but also pivotal hubs linking metabolic remodeling to disease progression. A deeper understanding of their mechanisms and targeted interventions is expected to provide new insights for therapeutic strategies against metabolic diseases.
Correction to "Rab14-Mediated Lipophagy Disrupts Lipid Homeostasis in Granulosa Cells and Impairs Female Fertility".
FASEB J · 2026 Jun · PMID 42281406 · Publisher ↗
Abstract loading — click title to view on PubMed.
A Novel Role of Smyd2 in Inflammatory Bowel Disease by Orchestrating Macrophage Polarization.
Tang C, Zhang H, Yu X … +2 more , Xiong L, Lei X
FASEB J · 2026 Jun · PMID 42274007 · Publisher ↗
Inflammatory bowel disease (IBD) is a chronic condition caused by an abnormal immune response to gut microflora that leads to inflammation in the gastrointestinal tract. Intestinal macrophages are emerging as key players...
Inflammatory bowel disease (IBD) is a chronic condition caused by an abnormal immune response to gut microflora that leads to inflammation in the gastrointestinal tract. Intestinal macrophages are emerging as key players in IBD pathogenesis. Especially, inflammatory M1 macrophages contribute to the onset and progression of IBD, whereas immunosuppressive M2 macrophages show protective activity against IBD. Orchestrating macrophage polarization is considered a potential therapeutic strategy for IBD, but it needs a better understanding of the mechanism underlying macrophage polarization in IBD. Here, we collected specimens from patients with IBD and established a dextran sodium sulfate (DSS)-induced murine colitis model to mimic human IBD. We observed that Smyd2 expression was reduced in both patients with IBD and mice with experimental colitis, and Smyd2 predominantly localized in macrophages. Then, we isolated mouse peritoneal macrophages and overexpressed Smyd2 in macrophages. We found that the overexpression of Smyd2 significantly repressed lipopolysaccharide (LPS)-induced M1 polarization but enhanced interleukin-4 (IL-4)-induced M2 polarization. Furthermore, overexpression of Smyd2 suppressed M1 polarization but promoted M2 polarization in mice with colitis. Collectively, Smyd2 orchestrates macrophage polarization in IBD. Our findings shed novel insight into the mechanism of macrophage polarization in IBD and suggest Smyd2 as a potential therapeutic target and prognosis biomarker for IBD.
IRF-1 Links Cytoskeletal Contraction With Inflammatory Response in mTOR-Inhibited Endothelial Cells.
Zhou Y, Zhang Z, Hu C … +5 more , Zhu X, Fan X, Zhang DM, Passerini AG, Sun C
FASEB J · 2026 Jun · PMID 42273992 · Publisher ↗
Clinical therapies targeting mammalian target of rapamycin (mTOR) are associated with high rates of pneumonitis. Recent studies independently revealed the upregulation of the proinflammatory transcription factor interfer...
Clinical therapies targeting mammalian target of rapamycin (mTOR) are associated with high rates of pneumonitis. Recent studies independently revealed the upregulation of the proinflammatory transcription factor interferon regulatory factor-1 (IRF-1) by mTOR inhibition (mTORi) of endothelial cells (EC) and further highlighted a mechanism converging on myosin light chain (MLC) phosphorylation-dependent cytoskeletal dynamics in promoting the endothelial hyperpermeability and pulmonary inflammation caused by mTORi. This study investigated a role for this mechanism in linking the regulation of IRF-1 expression with downstream responses in mTOR-inhibited EC. IRF-1 was transcriptionally upregulated in cultured EC by treatment with mTOR inhibitor rapamycin or torin 1, or by silencing either Raptor or Rictor expression to disrupt mTOR complex 1 (mTORC1) or 2 (mTORC2). Inhibition of MLC kinase (MLCK) activity or activation of MLC phosphatase (MLCP) to suppress MLC phosphorylation, or direct inhibition of actin polymerization, attenuated IRF-1 expression as well as transcription of an array of proinflammatory cytokines. Moreover, IRF-1 in turn upregulated MLCK expression to enhance MLC phosphorylation and promote endothelial hyperpermeability in mTOR-inhibited EC. Consistent with these observations in culture, targeted endothelial deficiency of IRF-1 in mice significantly reduced lung edema and inflammation elicited by separate or combined treatment of rapamycin and lipopolysaccharide. In conclusion, activation of actomyosin contractility by mTORi upregulated IRF-1, which promoted the development of lung injury by mediating inflammation and hyperpermeability responses in EC.
miR-204-5p Promotes Hepatogenic Differentiation of Adipose-Derived Stem Cells to Ameliorate Acute Liver Failure via the MDM2/E2F8/BMP4 Axis.
Bi M, Dai B, Sha R … +4 more , Hao X, Chen X, Du C, Wang Z
FASEB J · 2026 Jun · PMID 42273952 · Publisher ↗
Acute liver failure (ALF) is characterized by extensive hepatocyte necrosis and limited treatment options. Adipose-derived stem cells (ADSCs) show potential for liver regeneration, yet the mechanisms regulating their hep...
Acute liver failure (ALF) is characterized by extensive hepatocyte necrosis and limited treatment options. Adipose-derived stem cells (ADSCs) show potential for liver regeneration, yet the mechanisms regulating their hepatic differentiation remain unclear. Human ADSCs were infected with lentiviruses to overexpress or silence miR-204-5p, Murine double minute 2 (MDM2), E2F transcription factor 8 (E2F8), or bone morphogenetic protein 4 (BMP4). qPCR, immunofluorescence, and western blot detected mRNA and protein levels of hepatic markers-including hepatocyte nuclear factor 4 alpha (HNF4α), albumin (ALB), and alpha-fetoprotein (AFP). Periodic acid-Schiff (PAS) staining assessed glycogen storage, while enzyme-linked immunosorbent assay (ELISA) measured ALB and urea secretion. Dual-luciferase reporter and co-immunoprecipitation (Co-IP) assays verified molecular interactions and ubiquitination. A Carbon Tetrachloride (CCl₄)-induced ALF model in mice was adopted to investigate the therapeutic potential of miR-204-5p-overexpression ADSCs by fluorescence imaging, histology, tunel staining, and measurement of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. In vitro, miR-204-5p suppresses MDM2 expression, thereby reducing MDM2-mediated ubiquitination and degradation of E2F8. Stabilized E2F8 transcriptionally activates BMP4, ultimately promoting the hepatogenic differentiation of ADSCs, as evidenced by increased ALB and HNF4α expression, enhanced glycogen synthesis, and elevated urea production. In a CCl₄-induced ALF mouse model, miR-204-5p-modified ADSCs localized to the liver, reduced necrosis and apoptosis, improved hepatic architecture, and decreased ALT and AST levels. miR-204-5p promotes hepatogenic differentiation of ADSCs and ameliorates acute liver failure through the MDM2/E2F8/BMP4 signaling axis, providing a potential molecular target to enhance stem cell-based liver regeneration therapy.
3,4-Dimethoxychalcone Protects Against Steroid Induced Femoral Head Necrosis by Suppressing Ferroptosis via Activation of STAT3-Nrf2 Signaling Pathway.
Han LJ, Miao JS, Wu SH … +9 more , Zhan JN, Tan GC, Yang JF, Zhang LW, Wu ZH, Liu LY, Shang P, Xie CL, Liu HX
FASEB J · 2026 Jun · PMID 42268673 · Publisher ↗
Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a frequently encountered complication in orthopedic practice, yet its precise pathogenic mechanisms remain incompletely understood. Dysregulation of bo...
Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a frequently encountered complication in orthopedic practice, yet its precise pathogenic mechanisms remain incompletely understood. Dysregulation of bone metabolism induced by glucocorticoids (GCs) is considered a key contributing factor. 3,4-Dimethoxychalcone (3,4DC), an organic compound, has shown potential biological activities, but its role in the context of GIONFH has not been elucidated. This study investigates the protective effects and underlying mechanisms of 3,4DC against dexamethasone (Dex)-induced ferroptosis and its therapeutic potential in GIONFH.A rat model of GIONFH was established through intraperitoneal administration of Dex, and in vitro studies were performed by culturing osteoblasts (OBs) under Dex treatment conditions. To evaluate the effects of 3,4DC on Dex-treated OBs, we employed C11-BODIPY and FerroOrange staining, assessed mitochondrial function, and analyzed protein expression via Western blot and immunofluorescence. The impact of 3,4DC on the bone microarchitecture of the femoral head in rats was further examined using micro-CT, H&E staining, as well as immunofluorescence and immunohistochemistry at both imaging and histological levels. Our results indicate that 3,4DC effectively inhibits Dex-induced ferroptosis and attenuates the development of GIONFH. In vitro, 3,4DC treatment significantly increased glutathione (GSH) levels while reducing malondialdehyde (MDA) production, lipid peroxidation, and mitochondrial reactive oxygen species (ROS) accumulation. Furthermore, 3,4DC enhanced STAT3 phosphorylation, upregulated glutathione peroxidase 4 (GPX4) and osteogenesis-related proteins, and promoted bone formation. Mechanistically, 3,4DC activated the STAT3/Nrf2 signaling pathway. Notably, silencing STAT3 with siRNA abrogated the protective effects of 3,4DC in Dex-treated OBs.3,4DC alleviates GIONFH by activating the STAT3/Nrf2 signaling pathway, thereby suppressing ferroptosis and may have potential clinical applications.
Integrative Multi-Omics Analysis Elucidates the Progressive Disease Landscape and Reveals Dynamic Protein Biomarkers for MASLD Surveillance.
Liu K, Zhang B, Tang Y … +3 more , Tan Z, Bu Y, Lv Y
FASEB J · 2026 Jun · PMID 42268665 · Full text
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, encompassing a continuum ranging from simple steatosis to steatohepatitis, hepatic fibrosis, and cir...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, encompassing a continuum ranging from simple steatosis to steatohepatitis, hepatic fibrosis, and cirrhosis. Despite the complex and heterogeneous pathogenesis, effective therapeutic targets remain elusive. In this study, we sought to identify and validate critical genes implicated in MASLD progression through multi-omics integration and machine learning algorithms. Analysis revealed considerable activation of lipid metabolism, oxidative stress, and inflammation-related pathways throughout disease progression, with notable upregulation of AKR1B10, COL1A2, and SPP1 and downregulation of CYP2C19. These expression patterns were consistently verified across in vivo and in vitro models. Functional assays indicated that AKR1B10 knockdown or CYP2C19 overexpression substantially attenuated hepatocellular lipid accumulation, alleviated oxidative stress and inflammatory responses, and suppressed key lipogenic gene expression. Collectively, these findings elucidate key molecular axes in MASLD progression and provide mechanistic insights and theoretical foundations for the development of targeted therapies.
The Deficiency of USP20 Alleviates Pressure Overload-Induced Cardiac Hypertrophy via the NF-κB Signaling Pathway.
Fan Z, Li D, Shi M … +11 more , Liu S, Yang L, Zhao M, Liu X, Zeng J, Ren F, Zhang Z, Wu S, Wang Y, Li L, Han L
FASEB J · 2026 Jun · PMID 42268599 · Publisher ↗
Ubiquitin-specific protease 20 (USP20) belongs to the ubiquitin-specific protease (USP) family, which represents the largest subfamily of deubiquitinating enzymes. It plays a critical role in regulating cellular signalin...
Ubiquitin-specific protease 20 (USP20) belongs to the ubiquitin-specific protease (USP) family, which represents the largest subfamily of deubiquitinating enzymes. It plays a critical role in regulating cellular signaling transduction, maintaining protein stability, and influencing the development of various diseases. This study revealed that USP20 expression was significantly upregulated in transverse aortic constriction (TAC)-induced hypertrophic hearts and in angiotensin II (AngII)-stimulated neonatal rat cardiomyocytes (NRCMs). This study aims to investigate the potential protective role of USP20 deficiency in pressure overload-induced cardiac hypertrophy and to elucidate the underlying molecular mechanisms. Pathological cardiac hypertrophy was induced in mice via transverse aortic constriction (TAC) surgery. Following the procedure, relevant groups of mice were administered shUSP20 adenovirus via tail vein injection, with the TAC intervention lasting 28 days. The results showed that USP20 significantly exacerbated TAC-induced cardiomyocyte apoptosis and inflammatory responses, while simultaneously impairing cardiac function and aggravating myocardial hypertrophy. In vitro experiments further confirmed that USP20 markedly aggravated angiotensin II (AngII)-induced cardiomyocyte hypertrophy. Moreover, USP20 enhanced inflammatory responses and apoptosis levels in hypertrophic myocardium, as evidenced by increased levels of Bax, TNF-α, IL-6, and IL-1β, along with a decrease in Bcl2. Mechanistically, USP20 elevated the phosphorylation level of P65, and the protective effect of USP20 knockdown against AngII-induced cellular hypertrophy was further enhanced by co-treatment with the NF-κB inhibitor Bay11-7082. USP20 exacerbates cardiac hypertrophy by promoting P65 phosphorylation, which subsequently enhances the release of inflammatory cytokines and apoptotic proteins.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe