Fang Zhang

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most prevalent chronic liver disease worldwide, affecting both obese and non-obese individuals. While the reduced levels of circulating growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been consistently observed in patients with hepatic steatosis, the molecular role of hepatic growth hormone receptor (GHR) in MAFLD pathogenesis remains unclear. In this study, we established a liver-specific Ghr knockout (LGHRKO) mouse model that faithfully recapitulates non-obese MAFLD, characterized by hepatomegaly, elevated serum lipids and transaminases, and pronounced hepatic lipid accumulation, all occurring in the absence of obesity or increased adiposity. Mechanistically, LGHRKO livers displayed enhanced lipogenesis, impaired lipolysis, and upregulated cluster of differentiation 36 (CD36) expression, thereby driving hepatic lipid deposition. Single-cell RNA sequencing (scRNA-seq) further revealed hepatocyte-specific transcriptional alterations, including activation of lipid metabolic pathways and dysregulation of autophagy-related processes, providing insights into the cellular mechanisms underlying disease progression. Complementary human genetic analyses, including two-sample Mendelian randomization (MR) and genome-wide association studies (GWASs), demonstrated a causal relationship between impaired GH–IGF signaling and susceptibility to MAFLD, thereby bridging experimental observations with human disease risk. Collectively, our findings identify hepatic GHR deficiency as a key driver of non-obese MAFLD, establish LGHRKO mice as a valuable model for mechanistic and therapeutic studies, and underscore the translational significance of GH–IGF signaling in metabolic liver disease.

Thyroid eye disease (TED), the leading adult orbital disease, is an autoimmune disorder characterized by fibrosis. Effective anti‐fibrotic treatments are scarce, except for orbital decompression surgery involving orbital adipose tissue (OAT) removal, due to high rates of drug resistance following hyperthyroidism treatment and the lack of suitable mouse models. Understanding the mechanisms behind fibrotic remodeling of OAT could aid mouse model development and identify novel therapies. In the present study, stromal vascular fraction cells of OAT from patients with inactive‐stage TED, characterized by pronounced fibrosis, are analyzed at single‐cell resolution. platelet‐derived growth factor receptor (PDGFR)α ⁺ dipeptidyl peptidase (DPP)4 ⁺ fibroblasts exhibiting progenitor characteristics and fibrotic potential at the transcriptional level are identified. PDGFRα ⁺ DPP4 ⁺ fibroblasts showed the strongest interactions with macrophages, particularly M2 macrophages, which are enriched and topographically localized within the fibrotic area. Moreover, M2 macrophages promoted extracellular matrix production in PDGFRα ⁺ DPP4 ⁺ cells via the Growth arrest specific (GAS)6‐AXL Receptor Tyrosine Kinase (AXL) signaling pathway. Using a specific AXL inhibitor or AXL knockdown, fibrosis is substantially reduced in PDGFRα ⁺ DPP4 ⁺ fibroblasts in vitro, and in patient cell‐derived orthotopic xenograft models established via GAS6. By identifying pro‐fibrotic intercellular networks in OAT, these findings establish a rapid and repeatable mouse model of TED fibrosis and propose the GAS6‐AXL axis as a potential therapeutic target for TED.

Elevated glucocorticoid levels are common in conditions such as aging, chronic stress, Cushing syndrome, and glucocorticoid therapy. While glucocorticoids suppress inflammation through the glucocorticoid receptor (GR), they also cause metabolic side effects. Investigating alternative pathways beyond GR activation is crucial for reducing these side effects. Our phosphoproteomics analysis revealed that glucocorticoid exposure promotes phosphorylation at the RxxS motifs of multiple proteins in preadipocytes, including those mediated by serum- and glucocorticoid-induced kinase 3 (SGK3). SGK3 is a key mediator of glucocorticoid-induced adipogenesis, as shown by impaired adipogenesis after SGK3 inhibition or genetic ablation. Sgk3 -KO mice were resistant to obesity induced by glucocorticoid or a high-fat diet, and proteolysis targeting chimeras (PROTAC) targeting SGK3 reduced adipogenesis in both obese mice and in a thyroid eye disease cell line. Mechanistically, SGK3 translocated to the nucleus upon glucocorticoid stimulation, interacted with and phosphorylated the BRG1 subunit of the BAF complex, and prevented BRG1 degradation, promoting chromatin remodeling necessary for adipogenesis. These findings highlight SGK3 as a potential therapeutic target to mitigate metabolic side effects of elevated glucocorticoid levels.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune orbital disease influenced by multiple factors, including genetic and immune factors. The enlargement of orbital fat tissues are mainly due to abnormal activation of adipocyte differentiation. Epigenetic modifications provide mechanistic insight for regulating gene expression and cellular differentiation. Lysine specific demethylase 1 (LSD1) is reported in regulation of adipogenesis. Therefore, it is critical to investigate the relationship between epigenetic modifier LSD1 and histone modification level during TAO process. In this study, combined with the clinic study and highthrough sequencing approach, our results revealed that the volume of orbital fat tissue was lower in TAO patients compared to non-TAO patients, whereas the number of adipocytes was higher in TAO patients compared to non-TAO patients, the expression level of adipocyte differentiation markers were higher in TAO samples. Consistently, at the cellular system, the expression level of adipogenic markers were higher in the TAO derived cells compared with the non-TAO cells. And we found LSD1 was highly expressed in TAO-derived cells. However, knocking down LSD1 decreased the expression of adipocyte markers. Mechanistically, LSD1 promoted adipocyte gene activation by demethylating H3K9me2 at the promoter regions. Finally, treatment with pargyline, an LSD1 inhibitor, inhibited adipogenesis in a dose-dependent manner, and the same inhibition of adipogenesis results were obtained with treatment with teprotumumab alone or combined with pargyline. Overall, our study indicates that epigenetic modifications were dysregulated in TAO process, and these data elucidated a novel mechanism of adipocyte differentiation during TAO progression and positioned LSD1 as a potential anti-adipogenesis target in TAO. Further understanding of the interaction betwen transcription factors and epigeneic modifiers or other histone modifications in TAO is essential for providing new perspectives in TAO mechanistic study and clinical intervention.

Background Ferritin, a key indicator of body iron levels, has been reported to associate with type 2 diabetes (T2DM) and the onset of Gestational diabetes mellitus (GDM). However, limited research explores the association between mid-pregnancy ferritin levels and the risk of postpartum abnormal glucose metabolism (AGM) in patients with GDM. Methods A retrospective cohort study was conducted in 1514 women with GDM recruited from January 2016 to January 2021, and 916 women were included. Demographic characteristics, medical history and family history, pregnancy complications were recorded. Multiple logistic regression models were performed to assess the association between mid-pregnancy ferritin levels and the risk of postpartum AGM. Results Following the postpartum oral glucose tolerance test, 307 (33.5%) exhibited AGM. The AGM group had higher mid-pregnancy serum ferritin levels [AGM vs NGT: 23 (11.7, 69) µg/L vs 17.80 (9.85, 40.7) µg/L, P < 0.001] and had a larger proportion of women with ferritin levels ≥30 µg/L (AGM vs NGT: 43.6% vs 31.4%, P < 0.001). Logistic regression analysis demonstrated that women with ferritin levels≥ 30 µg/L had a 1.566 times higher risk of developing postpartum AGM. Conclusions These findings indicate that elevated mid-pregnancy ferritin levels are significantly and independently associated with increased postpartum AGM risk in women with previous GDM. Consequently, cautious consideration is necessary for prescribing iron supplements in prenatal care, particularly for non-anemic women with GDM at high risk of developing diabetes after delivery.

Diabetic retinopathy (DR) is a leading cause of irreversible blindness in the working‐age populations. Despite decades of research on the pathogenesis of DR for clinical care, a comprehensive understanding of the condition is still lacking due to the intricate cellular diversity and molecular heterogeneity involved. Single‐cell RNA sequencing (scRNA‐seq) has made the high‐throughput molecular profiling of cells across modalities possible which has provided valuable insights into complex biological systems. In this review, we summarise the application of scRNA‐seq in investigating the pathogenesis of DR, focusing on four aspects. These include the identification of differentially expressed genes, characterisation of key cell subpopulations and reconstruction of developmental ‘trajectories’ to unveil their state transition, exploration of complex cell‒cell communication in DR and integration of scRNA‐seq with genome‐wide association studies to identify cell types that are most closely related to DR risk genetic loci. Finally, we discuss the future challenges and expectations associated with studying DR using scRNA‐seq. We anticipate that scRNA‐seq will facilitate the discovery of mechanisms and new treatment targets in the clinical care landscape for patients with DR.Key points: Progress in scRNA‐seq for diabetic retinopathy (DR) research includes studies on DR patients, non‐human primates, and the prevalent mouse models. scRNA‐seq facilitates the identification of differentially expressed genes, pivotal cell subpopulations, and complex cell‐cell interactions in DR at single‐cell level. Future scRNA‐seq applications in DR should target specific patient subsets and integrate with single‐cell and spatial multi‐omics approaches.

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among the working-age population. Microglia, resident immune cells in the retina, are recognized as crucial drivers in the DR process. Microglia activation is a tightly regulated immunometabolic process. In the early stages of DR, the M1 phenotype commonly shifts from oxidative phosphorylation to aerobic glycolysis for energy production. Emerging evidence suggests that microglia in DR not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system. This redox adaptation supports metabolic reprogramming and offers potential therapeutic strategies using antioxidants. Here, we provide an overview of recent insights into the involvement of reactive oxygen species and the distinct roles played by key cellular antioxidant pathways, including the NADPH oxidase 2 system, which promotes glycolysis via enhanced glucose transporter 4 translocation to the cell membrane through the AKT/mTOR pathway, as well as the involvement of the thioredoxin and nuclear factor E2-related factor 2 antioxidant systems, which maintain microglia in an anti-inflammatory state. Therefore, we highlight the potential for targeting the modulation of microglial redox metabolism to offer new concepts for DR treatment.