The insulin family consists of insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2), their receptors (IR, IGF-1R and IGF-2R), and their binding proteins. All three ligands are involved in cell proliferation, apoptosis, protein synthesis and metabolism due to their homologous sequences and structural similarities. Insulin-like growth factor 2, a member of the insulin family, plays an important role in embryonic development, metabolic disorders, and tumorigenesis by combining with three receptors with different degrees of affinity. The main pathological feature of various fibrotic diseases is the excessive deposition of extracellular matrix (ECM) after tissue and organ damage, which eventually results in organic dysfunction because scar formation replaces tissue parenchyma. As a mitogenic factor, IGF-2 is overexpressed in many fibrotic diseases. It can promote the proliferation of fibroblasts significantly, as well as the production of ECM in a time- and dose-dependent manner. This review aims to describe the expression changes and fibrosis-promoting effects of IGF-2 in the skin, oral cavity, heart, lung, liver, and kidney fibrotic tissues.

Phosphodiesterase 2 (PDE2A) modulates the levels of cAMP/cGMP and was recently found to be involved in mitochondria function regulation, closely related to multiple types of tumor progression. This study aimed to estimate the prognostic significance and biological effects of PDE2A on hepatocellular carcinoma (HCC). We comprehensively analyzed the PDE2A mRNA expression in HCC based on The Cancer Genome Atlas (TCGA) database and investigated the effects of PDE2A on the proliferation and metastatic capacity of HCC cells. PDE2A was downregulated in 25 cancer types, including HCC. Lower PDE2A expression was a protective factor in HCC and was negatively associated with serum AFP levels, tumor status, vascular invasion, histologic grade, and pathologic stage of HCC. Moreover, tumors with low PDE2A expression displayed a decreased immune function. Then, the ROC curve was used to assess the diagnostic ability of PDE2A in HCC (AUC = 0.823 in TCGA and AUC = 0.901 in GSE76427). Patients with low PDE2A expression exhibited worse outcomes compared with those with high PDE2A expression. Additionally, GO functional annotations demonstrated the involvement of PDE2A in the ECM organization, systems development, and ERK-related pathways, indicating that PDE2A might regulate HCC growth and metastasis. The in vitro experiments confirmed that overexpression of PDE2A inhibited proliferation, colony formation, migration, and invasion in two HCC cell lines (HLF and SNU-368), while inhibition of PDE2A has the opposite results. The mechanism of PDE2A’s effect on HCC cells is attributed to the change of mitochondrial morphology and ATP content. These data demonstrated that PDE2A closely participated in the regulation of HCC proliferation and metastasis and can be used as a predictive marker candidate and a potential therapeutic target for HCC.

Background: Skin fibrosis encompasses a spectrum of disorders and includes hypertrophic scar (HTS), keloid scar (KS), and systemic sclerosis (SSc), but the pathogenic fibroblast states and shared upstream regulators contributing to these conditions remain incompletely defined. As a common form of skin fibrosis, HTS provides a useful model for elucidating fibroblast heterogeneity and mechanism-based therapeutic vulnerability across skin fibrosis diseases. This study aimed to define the role of RUNX1 in pathogenic POSTN+ fibroblasts during skin fibrosis and to investigate the underlying stress-adaptive and microenvironment-remodeling mechanisms. Methods: We performed single-cell RNA sequencing, spatial transcriptomic analysis, multiomics profiling, and cell–cell communication analysis to identify pathogenic fibroblast subpopulations and their regulatory networks in HTS. RUNX1-centered mechanisms were analyzed by CUT&Tag, RNA sequencing, rescue experiments, and functional assays, followed by in vitro and in vivo validation. High-throughput virtual screening and structural analyses were used to computationally prioritize candidate compounds predicted to bind to POSTN that are relevant to the RUNX1-high POSTN+ fibroblast state. Results: The integrated analyses revealed a significantly expanded RUNX1-high POSTN+ fibroblast subpopulation in HTS and KS. RUNX1 expression was consistently elevated across human skin fibrosis diseases and experimental models of skin fibrosis. Mechanistically, RUNX1 increased the pathogenic properties of POSTN+ fibroblasts by activating ATF4 and POSTN. Through ATF4, RUNX1 increased endoplasmic reticulum stress adaptation and ferroptosis resistance, thereby supporting the ability of POSTN+ fibroblasts to remain activated under stress. Through POSTN, RUNX1 further reinforced fibroblast activation and matrix remodeling. Furthermore, RUNX1 transcriptionally activated MDK, which promoted angiogenesis-associated microenvironmental remodeling through paracrine signaling. Our computational analysis prioritized berberine (BBR) as a candidate compound predicted to bind to POSTN and BBR suppressed RUNX1/POSTN-associated stress-adaptive and profibrotic features in hypertrophic scar fibroblasts. In vivo validation using a bleomycin-induced skin fibrosis mouse model and a mouse scar model supported the antifibrotic potential of targeting RUNX1, and BBR reduced scar formation in a rabbit ear hypertrophic scar model, demonstrating its antiscar therapeutic efficacy. Conclusion: RUNX1 serves as a universal marker and actionable upstream regulator in skin fibrosis diseases. RUNX1-high POSTN+ fibroblasts may contribute to skin fibrosis by increasing the adaptation to ATF4-associated endoplasmic reticulum stress, ferroptosis resistance, persistent fibroblast activation, and vascular microenvironmental remodeling. BBR therefore represents a potential candidate predicted to bind to POSTN for skin fibrosis treatment.