Lexun Wang

CCAAT/enhancer-binding protein δ (C/EBPδ) is a rapidly responsive transcription factor that occupies an important regulatory position in adipocytes. Induced during the early stage of adipocyte differentiation, C/EBPδ integrates hormonal, inflammatory, metabolic, and stress-related cues and contributes to the coordination of downstream transcriptional and functional programs. Beyond its role in the initiation of differentiation, C/EBPδ is also involved in adipogenic progression, metabolic regulation, and immune-related functions in adipocytes. Current evidence indicates that C/EBPδ participates in early adipogenic regulatory networks, contributes to lipid metabolic programs, and is associated with immune-regulatory processes linked to lipid antigen presentation. Notably, the biological output of C/EBPδ is strongly shaped by tissue type, developmental stage, and microenvironmental context, ranging from promotion of adipogenic differentiation to regulation of inflammatory, metabolic, and adaptive stress responses under distinct physiological and pathological conditions. This review summarizes the upstream regulatory network, downstream functional framework, and context-dependent roles of C/EBPδ in adipocytes, and further discusses its potential relevance to adipose-related diseases as well as the opportunities and challenges for future precision intervention strategies.

As ubiquitous innate immune cells, macrophages are crucial for tissue homeostasis and disease pathogenesis. Although our understanding of macrophage subsets and functions has advanced, no effective strategies are available for targeting macrophages to treat diseases in clinical settings due to their heterogeneity. Transcription factors that regulate macrophage function have received increasing attention. CCAAT/enhancer-binding protein delta (CEBPD), an inflammation-associated transcription factor characterized by low basal expression but rapid induction by stimuli, has emerged as a key regulator of macrophages. CEBPD governs diverse biological processes in macrophages through its target genes. Furthermore, macrophage CEBPD significantly contributes to various pathologies. Modulating CEBPD expression or activity in macrophages could regulate various molecular processes to improve disease progression and alleviate organ damage; therefore, novel CEBPD-based therapeutic methods for treating diseases have attracted attention. In this review, we describe the factors upstream and downstream of CEBPD in macrophages. We then summarize recent advances in the regulation of macrophage biological processes by CEBPD. Finally, we discuss the contribution of macrophage CEBPD to various diseases and highlight strategies for developing novel therapies to modulate macrophage function by targeting CEBPD.

CCAAT/enhancer-binding protein delta (CEBPD), as an evolutionarily conserved protein in mammals, belongs to the CEBP transcription factor family, which modulates many biological processes. The diversity of CEBPD functions partly depends on the cell type and cellular context. Aberrant CEBPD expression and activity are associated with multiple organ diseases, including cardiovascular diseases. In this review, we describe the basic molecular biology of CEBPD to understand its expression regulation, modifications, and functions. Here, we summarize the recent advances in genetically modified animals with CEBPD. Finally, we discuss the contribution of CEBPD to cardiovascular diseases and highlight the strategies for developing novel therapies targeting CEBPD.

Background: Cardiac fibroblasts (CFs) play a vital role in the physiological and pathological processes of the heart. Previous studies have demonstrated that high glucose stimulation induces the transformation of CFs into myofibroblasts, contributing to cardiac fibrogenesis. However, in vivo experiments have predominantly utilized adult animals, whereas most in vitro studies have focused on CFs derived from neonatal animals. The responses of CFs from different age groups to high glucose levels remain unclear. This study aimed to investigate transcriptional alterations in CFs at distinct developmental stages in response to high glucose exposure. Methods: CFs were isolated from neonatal (S1, 0–3 days), juvenile (S2, 3–4 weeks), adult (S3, 10–13 weeks), and aged (S4, 20 months) rats. CFs were exposed to normal (5.5 mM, NG) or high glucose (33 mM, HG). The cellular RNA was extracted for sequencing and analysis. Differentially expressed genes (DEGs) were validated by quantitative real-time PCR. Results: After NG treatment, fibrosis and inflammation-related gene expression in CFs (e.g., Col8a1, Col8a2, IL-6, Ccl2, Ccl20, Mmp2 and Mmp9) increased with age, while proliferation-related genes (MCM family, Sox10, Sox11) decreased. HG treatment most affected S3-CFs, showing 228 DEGs; it suppressed growth-related genes (Adra1d, Htr2b) and enhanced inflammatory genes (IL-6, Olr1). In S1-CFs, 197 inflammation-rich genes were upregulated under HG. S4-CFs displayed 166 DEGs, mostly metabolic downregulation (G6pc). S2-CFs had the fewest DEGs (112), focusing on cell metabolism. Conclusions: Fibrosis- and inflammation-associated gene expression in CFs showed an age-dependent stepwise elevation. CFs from distinct developmental stages responded differently to HG stimulation, with S3-CFs exhibiting the most pronounced response. These findings highlight the developmental characteristics of CFs and provide implications for the selection of appropriate CFs to investigate diabetes-associated cardiac fibrosis.

This study focused on exploring the effects of SW033291, an inhibitor of 15-hydroxyprostaglandin dehydrogenase, on type 2 diabetes mellitus (T2DM) mice from a comprehensive perspective. Studies have demonstrated that SW033291 benefits tissue repair, organ function, and muscle mass in elderly mice. Our recent investigation initially reported the beneficial effect of SW033291 on T2DM progression. Herein, we used a T2DM mouse model induced by a high-fat diet and streptozotocin injection. Then, serum and liver metabolomics, as well as liver transcriptomic analyses, were performed to provide a systematic perspective of the SW033291-ameliorated T2DM. The results indicate SW033291 improved T2DM by regulating steroid hormone biosynthesis and linoleic/arachidonic acid metabolism. Furthermore, integrated transcriptomic and metabolomic analyses suggested that key genes and metabolites such as Cyp2c55, Cyp3a11, Cyp21a1, Myc, Gstm1, Gstm3, 9,10-dihydroxyoctadecenoic acid, 11-dehydrocorticosterone, and 12,13-dihydroxy-9Z-octadecenoic acid played crucial roles in these pathways. qPCR analysis validated the significant decreases in the hepatic gene expressions of Cyp2c55, Cyp3a11, Myc, Gstm1, and Gstm3 in the T2DM mice, which were reversed following SW033291 treatment. Meanwhile, the elevated mRNA level of Cyp21a1 in T2DM mice was decreased after SW033291 administration. Taken together, our findings suggest that SW033291 has promising potential in alleviating T2DM and could be a novel therapeutic candidate.

Macrophages have a wide variety of roles in physiological and pathological conditions, making them promising diagnostic and therapeutic targets in diseases, especially metabolic disorders, which have attracted considerable attention in recent years. Owing to their heterogeneity and polarization, the phenotypes and functions of macrophages related to metabolic disorders are diverse and complicated. In the past three decades, the rapid progress of macrophage research has benefited from the emergence of specific molecular markers to delineate different phenotypes of macrophages and elucidate their role in metabolic disorders. In this review, we analyze the functions and applications of commonly used and novel markers of macrophages related to metabolic disorders, facilitating the better use of these macrophage markers in metabolic disorder research.