Qin Pan

Introduction: Airway remodeling represents a key pathological feature of severe asthma. Although the interleukin-13 (IL-13) R130Q variant is associated with increased disease severity, its specific contribution to airway remodeling remains unclear. Methods: This study used an ovalbumin (OVA)-induced asthma model in which mice were sensitized intraperitoneally with OVA/alum and subsequently challenged intranasally with OVA; human IL-13 130R or IL-13 130Q was administered intranasally before each challenge. Primary human bronchial smooth muscle cells (hBSMCs) from a single healthy donor were treated with both variants to assess CCK-8-derived proliferative/metabolic activity, migration, acetylcholine (ACh)-induced intracellular calcium responses, and IL-4 and IL-5 concentrations in culture supernatants. JAK2 and STAT6 phosphorylation was evaluated separately as a downstream signaling readout. Structural modeling and independent triplicate 100-ns molecular dynamics simulations of the IL-13/IL-13 receptor alpha 2 (IL-13Rα2) complex were performed using GROMACS 2025.4 with the AMBER ff19SB force field, and molecular mechanics/generalized Born surface area analysis was used for relative comparison of binding free energies. Results: IL-13 130Q produced limited airway changes in mice without OVA sensitization, but exacerbated airway wall thickening, luminal narrowing, smooth-muscle expansion, and pulmonary inflammation in OVA-sensitized and intranasally challenged mice. In hBSMCs, IL-13 130Q induced greater CCK-8-derived proliferative/metabolic activity, migration, ACh-induced intracellular calcium responses, and IL-4 and IL-5 concentrations than IL-13 130R at 10 -100 ng/mL. Molecular dynamics analyses suggested the reduced binding stability of IL-13 130Q/IL-13Rα2 complex, as reflected by fewer interfacial hydrogen bonds, altered intermolecular contacts, and a less favorable relative binding free energy. Elevated JAK2/STAT6 phosphorylation indicated the amplification of downstream signaling, mechanistically tied to potential reduced decoy-receptor affinity. Conclusion: These preclinical data support a contextdependent potentiating function of IL13 130Q in airway smoothmuscle phenotypic modulation and airway remodeling. Further investigation may rationalize genotype-based stratification in the therapy of severe asthma.

Aims: This exploratory study aimed to identify the effects of SIRT1 polymorphisms on the serum lipidomic profile and pathological characteristics in metabolic dysfunction-associated steatotic liver disease (MASLD). Materials: Chinese Han patients with biopsy-proven MASLD were genotyped for the single nucleotide polymorphisms (SNPs) in SIRT1 . Lipidomics based on untargeted ultra-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS) was applied to map the SIRT1 -driven serum lipid signature, followed by correlation analyses linking these lipid traits to hepatic steatosis, ballooning, lobular inflammation, and fibrosis. Integrative pathological scoring finally explored how SIRT1 variants that remodel circulating lipids may be associated with MASLD-specific histological change. Results: SIRT1 SNPs (rs3740053, rs2394443, rs2236318, rs7896005, rs2273773, rs2394445, and rs2394446) demonstrated extensive association with serum lipidomics of MASLD patients. SIRT1 rs2236318, rs7896005, and rs2394445, affecting 2, 7, and 7 serum triacylglycerols (TAGs) respectively, dominated the SIRT1 SNP-lipidomics association. Quantitative analysis revealed significantly elevated TAGs levels (48:0, 50:0, 50:1, 52:0, 52:1, 52:2, and 54:1), the most abundant species, in MASLD patients with rs2394445 A/A genotype compared with A/T+T/T. These elevated rs2394445-dependent TAG levels were associated with high-grade hepatic steatosis (rho: 0.367 to 0.540, p < 0.033–0.001) rather than ballooning, lobular inflammation, or fibrosis. The significant correlation of rs2394445 A/A genotype with severe steatosis suggested a potential pathological link through TAG profile modulation. In contrast, rs2394445 showed a limited effect on total circulating lipids and obesity indices (BMI, WHtR). Conclusion: The A/A genotype at SIRT1 rs2394445 is associated with elevated serum TAGs containing saturated or monounsaturated fatty acids, which are linked to high-grade hepatic steatosis in MASLD independently of obesity.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a critical step in the progression from simple fatty liver disease to more severe conditions such as cirrhosis and hepatocellular carcinoma, and it remains difficult to treat. Arctigenin (ATG), a monomer of Fructus Arctii, exhibits anti-inflammatory activity. Therefore, we aimed to examine its potential protective role against MASH and explore the underlying mechanisms.

Purpose: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a relapsing-and-remitting cycle. Mucosal healing is a critical predictor of long-term outcomes; however, the discordance between mucosal healing at different depths and clinical activity complicates UC management. Patients and Methods: Cell death-related genesets (CDRGs) were analyzed in UC patients, with grouping using unsupervised hierarchical clustering. Concordance between grouping methods was assessed using Cohen’s Kappa and Sankey plots. The predictive value was quantified using the area under the curve. Subgroup analysis explored the additive effects and intrinsic associations between the CDRG-based grouping and other grouping methods. Differentially expressed genes (DEGs) were identified using Wilcoxon test. Robustness was validated in 3 independent cohorts. Single-cell analysis was used to assess cell type-specific impacts. Cytokine expression in colon organoids was measured using RT-qPCR. Results: CDRGs’ activities effectively predicted the clinical, histological, and endoscopic grouping. CDRG-based grouping emerged as an independent predictor, resolving inconsistence between histological and clinical grouping and improving concordance across clinical, histological, and endoscopic grouping. Integrating endoscopic or histological grouping with CDRG-based grouping improved the predictive value for clinical activity. CDRGs were intrinsically associated with DEGs, impacted non-immune cells, and reshaped immune cell infiltration through intercellular interactions. Epithelial cells were the main target of active CDRGs, exhibiting upregulated MIF, MDK, and LGALS9 in UC. In necroptotic colon organoids, MIF and MDK were significantly upregulated, whereas LGALS9 remained unchanged. Conclusion: CDRG-based grouping served as an independent predictor to improve the concordance between clinical, histological, and endoscopic grouping in UC, and was of potency to precisely identify UC patients achieving long-term treatment target, namely mucosal healing. Active CDRGs intrinsically associated with genetic and immunological alterations in UC, highlighting their potential as novel biomarkers and therapeutic targets.

Platelets are involved in hemostasis and immune regulation, but little is currently known regarding their role in inflammatory bowel disease. In the present study, the mechanism by which platelet activation affects macrophage C‑X‑C motif chemokine receptor 3 (CXCR3) by releasing platelet factor 4 (PF4), thus aggravating ulcerative colitis (UC) disease progression, was investigated. A dextran sulfate sodium‑induced mouse model showed co‑localization of the platelet marker PF4 with the macrophage M1 marker inducible nitric oxide synthase. Furthermore, co‑culturing platelets with monocytes (THP‑1) in vitro led to the transformation of monocytes into macrophages, as well as the activation of macrophages exhibiting proinflammatory properties. Meanwhile, reverse transcription‑quantitative PCR (RT‑qPCR) showed that inflammatory factors, such as IL‑1β, IL‑6 and TNF‑α were significantly increased in macrophages after platelet co‑culture. It was therefore hypothesized that the PF4/CXCR3 pathway may serve an important role in cell‑to‑cell communication. Furthermore, intervention with PF4 in THP‑1 cells induced the M1 macrophage phenotype and inflammatory cytokine expression, which was consistent with co‑culturing, whereas inhibition of CXCR3 (AMG487) reversed the effects of PF4. In addition, following treatment with PF4, THP‑1 cells were found to be under oxidative stress and apoptosis was enhanced, as determined by detecting reactive oxygen species, mitochondrial membrane potential and Annexin‑V, as well as the classical apoptotic proteins Bcl‑2/Bax/caspase‑3 through western blotting. In addition, changes in MAPK and NF‑κB, two classic inflammatory signaling pathways, were detected. Furthermore, mice were treated with an anti‑platelet medication or CXCR3 inhibitor to observe in vivo inflammatory changes; through phenotypic assessment, immunofluorescence staining, RT‑qPCR and TUNEL assay, it was demonstrated that the PF4/CXCR3 pathway may aggravate inflammation in mice with UC. In conclusion, platelets and macrophages may interact in UC through the PF4/CXCR3 pathway to exacerbate inflammation, providing novel options for the treatment of UC.

Editorial: Interaction of endocrine disorders and metabolic associated fatty liver disease: the genetic and epigenetic basis

Nonalcoholic steatohepatitis (NASH) reflects the outcome of steatosis-based peroxidative impairment. Here, the effect and mechanism of γ-muricholic acid (γ-MCA) on NASH were investigated on the basis of its actions in hepatic steatosis, lipid peroxidation, peroxidative injury, hepatocyte apoptosis, and its NAFLD activity score (NAS). The agonist action of γ-MCA on farnesoid X receptor (FXR) upregulated the small heterodimer partner (SHP) expression of hepatocytes. An increase in SHP attenuated the triglyceride-dominated hepatic steatosis which was induced in vivo by a high-fat high-cholesterol (HFHC) diet and in vitro by free fatty acids depending on the inhibition of liver X receptor α (LXRα) and fatty acid synthase (FASN). In contrast, FXR knockdown abrogated the γ-MCA-dependent lipogenic inactivation. When compared to their excessive production in HFHC diet-induced rodent NASH, products of lipid peroxidation (MDA and 4-HNE) exhibited significant reductions upon γ-MCA treatment. Moreover, the decreased levels of serum alanine aminotransferases and aspartate aminotransferases demonstrated an improvement in the peroxidative injury of hepatocytes. By TUNEL assay, injurious amelioration protected the γ-MCA-treated mice against hepatic apoptosis. The abolishment of apoptosis prevented lobular inflammation, which downregulated the incidence of NASH by lowering NAS. Collectively, γ-MCA inhibits steatosis-induced peroxidative injury to ameliorate NASH by targeting FXR/SHP/LXRα/FASN signaling.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, associated with an outcome of hepatic fibrosis/cirrhosis and hepatocellular carcinoma. However, limited exploration of the underlying mechanisms hinders its prevention and treatment. To investigate the mechanisms of epigenetic regulation in NAFLD, the expression profile of circular RNA (circRNA) of rodents in which NAFLD was induced by a high-fat, high-cholesterol (HFHC) diet was studied. Modeling of the circRNA-microRNA (miRNA) -mRNA regulatory network revealed the functional characteristics of NAFLD-specific circRNAs. The targets and effects in the liver of such NAFLD-specific circRNAs were further assessed. Our results uncovered that the downregulation of 28 annotated circRNAs characterizes HFHC diet-induced NAFLD. Among the downregulated circRNAs, long intergenic non-protein coding RNA, P53 induced transcript (LNCPINT) -derived circRNAs (circ_0001452, circ_0001453, and circ_0001454) targeted both miR-466i-3p and miR-669c-3p. Their deficiency in NAFLD abrogated the circRNA-based inhibitory effect on both miRNAs, which further inactivated the AMPK signaling pathway via AMPK-α1 suppression. Inhibition of the AMPK signaling pathway promotes hepatic steatosis, depending on the transcriptional and translational upregulation of lipogenic genes, such as those encoding sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) in hepatocytes. The levels of LNCPINT-derived circRNAs displayed a negative association with hepatic triglyceride (TG) concentration. These findings suggest that loss of LNCPINT-derived circRNAs may underlie NAFLD via miR-466i-3p- and miR-669c-3p-dependent inactivation of the AMPK signaling pathway.

Long noncoding RNAs (lncRNAs) are key regulators of hepatic stellate cells (HSCs), yet the role of upregulated lncRNA-NONRATT013819.2 in activated HSCs remains uncertain. In this study, the effects of NONRATT013819.2 on proliferation, apoptosis, migration, and contraction of transforming growth factor (TGF)-β1-induced HSCs were investigated. The mechanisms of NONRATT013819.2 on the activated HSCs were explored by loss-of-function of NONRATT013819.2 and gain-of-function of the target gene. Here, TGF-β1 treatment resulted in a gradual increase in the expression of cytoskeleton markers (collagen, α-SMA, and TIMP1), NONRATT013819.2, miR24-3p, and lysyl oxidase (Lox) over time in HSCs. NONRATT013819.2 acted as a sponge of miR24-3p to competitively abolish the inhibition of the lox gene in HSCs. Silencing of NONRATT013819.2 suppressed the expression of cytoskeleton markers, proliferation, and the proportion of cells that entered the S-phase, and promoted apoptosis in TGF-β1-activated HSCs. These effects were reversed when lox overexpression was introduced simultaneously. Similarly, silencing of NONRATT013819.2 also blocked ECM reconstruction, while recused by lox overexpression in TGF-β1-activated HSCs. In conclusion, upregulation of NONRATT013819.2 promotes the myofibroblastic transition by competitively binding miR24-3p to release lox in HSCs. Therefore, targeted therapy of NONRATT013819.2 may have the potential for liver fibrosis.