Forkhead box P3 (FOXP3), the master regulator of regulatory T cells (Tregs), is aberrantly expressed in tumor cells, including lung cancer. Alternative splicing generates multiple isoforms, among which the full-length FOXP3 (FOXP3FL) and exon 3-deleted variant (FOXP3Δ3) are predominant. We identified FOXP3Δ3 as the major isoform in non-small cell lung cancer (NSCLC) tumor cells. FOXP3Δ3 expression was elevated in tumor tissues and correlated with larger tumor size and advanced T stage. Functional assays showed that tumoral FOXP3Δ3 enhanced proliferation, invasion, migration, stemness, and apoptosis resistance in NSCLC cells, exerting stronger effects than FOXP3FL. Knockdown of FOXP3Δ3 in NSCLC cells suppressed tumor growth in nude mice, confirming its oncogenic activity in vivo. Mechanistically, FOXP3Δ3 upregulated phosphorylated STAT3 and mesenchymal markers (N-cadherin, Vimentin, Snail), while reducing epithelial marker E-cadherin compared with FOXP3FL. Coimmunoprecipitation indicated these differences may arise from distinct STAT3 binding affinities. Additionally, FOXP3Δ3 decreased cisplatin-induced apoptosis, suggesting a role in chemoresistance. In summary, FOXP3Δ3 is the predominant oncogenic FOXP3 isoform in NSCLC tumor cells, promoting tumor cell progression and therapy resistance through STAT3 signaling. These findings highlight FOXP3Δ3 as a potential therapeutic target.
Connexins, a family of transmembrane proteins, are essential for intercellular communication in the mammalian central nervous system, particularly through their assembly into gap junction channels. This review explores the central role of connexin-mediated signalling in hypothalamic regulation of nutrient metabolism and energy homeostasis, together with the function of connexins in peripheral metabolic organs. Focusing on connexins Cx43 and Cx30, we discuss their specific expression within hypothalamic neuroglial populations, including astrocytes and tanycytes, and their involvement in glucose sensing, metabolic signalling, and neuroendocrine regulation. Functional studies demonstrate that hypothalamic Cx43 is dynamically regulated by metabolic status, while its knockdown impairs glucose-stimulated insulin secretion and systemic energy balance. Tanycytes, interconnected into a Cx43-dependent network, play a critical role in relaying metabolic cues from cerebrospinal fluid and blood to hypothalamic neurons, thereby orchestrating adaptive responses to glycaemic changes. The review further details how the disruption of connexin-mediated coupling in tanycytes leads to impaired glucose sensing, altered neuronal activity, and systemic metabolic disorders. Beyond the hypothalamus, this review also summarizes how connexins in peripheral metabolic organs contribute to metabolic homeostasis, inflammatory regulation, and disease progression. Collectively, these discoveries highlight the fundamental importance of connexins in integrating metabolic signals and maintaining systemic homeostasis.
Premature ovarian insufficiency (POI) causes early loss of ovarian function, though its underlying metabolic-epigenetic mechanisms remain unclear. Using ovarian tissues from POI patients and a cisplatin-induced mouse model, we investigated the role of the NAD+-dependent deacetylase Sirtuin 1 (SIRT1) in granulosa cells. We found that SIRT1 expression was markedly downregulated in POI, correlating with hyperacetylation of the glycolytic enzyme pyruvate kinase M2 (PKM2) and pathogenic lactate accumulation. Restoring SIRT1 activity via intra-ovarian AAV-SIRT1 delivery or systemic administration of nicotinamide mononucleotide (NMN) reversed these phenotypes. This intervention improved follicular development, reduced granulosa cell apoptosis, and normalized serum anti-Müllerian hormone and follicle-stimulating hormone levels. Mechanistically, SIRT1 directly interacts with and deacetylates PKM2, suppressing its activity and limiting lactate production. Our work defines a critical SIRT1-PKM2-lactate metabolic axis that maintains ovarian homeostasis. Targeting this axis via NAD+-boosting interventions, such as NMN, presents a promising novel therapeutic strategy for POI.
Abstract Bile acids (BAs) have evolved from their classical definition as digestive surfactants to be recognized as potent endocrine signaling molecules that orchestrate systemic metabolism. Through activation of nuclear receptors, such as farnesoid X receptor (FXR), and membrane receptors, such as G protein-coupled BA receptor 1 (GPBAR1/TGR5), BAs regulate glucose, lipid, immune, and energy homeostasis. Aging reshapes BA synthesis, enterohepatic circulation, hydrophobicity, microbial biotransformation, and receptor responsiveness, thereby linking BA metabolism to hepatic senescence, inflammaging, and age-associated liver vulnerability. In turn, dysregulated BA signaling can amplify mitochondrial stress, endoplasmic reticulum stress, impaired autophagy, immune dysfunction, and senescence-associated secretory phenotypes, suggesting a bidirectional relationship between BA remodeling and aging progression. This review critically examines the role of BAs as hormone-like mediators within the aging liver microenvironment, summarizes major BA species and receptor preferences, integrates gut microbiota–BA crosstalk, and evaluates the therapeutic potential and caveats of targeting the BA–FXR–TGR5 axis in aging-related liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), autoimmune liver diseases (AILD), chronic hepatitis B (CHB), and hepatocellular carcinoma (HCC).
