山东中医药大学

Therapeutic resistance remains a major cause of treatment failure and disease recurrence across cancer types, considerably limiting the long-term efficacy of chemotherapies, targeted therapies, and immunotherapies. Growing evidence indicates that resistance cannot be fully explained by static genetic alterations but rather arises from dynamic and reversible adaptive processes. Epigenetic regulation governs transcriptional plasticity, cellular state transitions, and tumor heterogeneity under therapeutic stress. Alterations in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA networks enable cancer cells to silence tumor suppressor programs, activate compensatory survival pathways, acquire stem cell-like drug-tolerant persister states, and remodel the tumor immune microenvironment. These mechanisms often act in a coordinated manner to form a dynamic regulatory system that supports adaptive resistance. However, current studies have frequently focused on individual epigenetic regulators and have lacked an integrated framework to explain how epigenetic plasticity collectively drives therapeutic resistance. In this review, we deconstruct cancer therapy resistance using the conceptual framework of the “epigenetic landscape.” We summarize the molecular functions and crosstalk among the major epigenetic layers and describe how this integrated network sustains key resistance-associated phenotypes. We also discuss emerging therapeutic strategies that target epigenetic plasticity, including epigenetic drugs, targeted protein degradation, epigenetic editing, and rational combination therapies. Overall, this review provides a systematic framework for understanding epigenetically mediated therapy resistance and highlights epigenetic plasticity as a therapeutic vulnerability for developing durable cancer treatments.

Metabolic diseases (MetDs), characterized by metabolic dysregulation leading to abnormal blood glucose, lipid, and uric acid levels, frequently result in organ damage, functional impairment, and multiple complications. These conditions severely compromise quality of life and increase mortality risk, constituting a major global health burden. Icariin (ICA), a major bioactive compound derived from Epimedium species, has demonstrated substantial therapeutic potential in the management of MetD. Accumulating evidence indicates that ICA exerts beneficial effects by improving insulin resistance and modulating oxidative stress, fibrosis, inflammatory responses, and lipid metabolism. Through these mechanisms, ICA influences the pathogenesis and progression of diabetes mellitus, osteoporosis, metabolic dysfunction–associated steatotic liver disease, obesity, and various metabolic disorders. This review provides a comprehensive summary of recent advances in the application of ICA for the management of MetD, focusing on its molecular mechanisms, clinical applications, and research prospects. The aim is to establish a solid foundation for optimizing the therapeutic use of ICA in the management of MetDs.

Idiopathic pulmonary fibrosis (IPF) represents a chronic, non-reversible, and irreversible interstitial lung disease with the lack of curative interventions and a poor prognosis; identifying safe and effective therapeutic agents is of paramount importance. The Ophiopogon-Ginseng herb pair, a classical traditional Chinese medicine (TCM), exerts Qi-replenishing and Yin-nourishing effects. Its active constituents Ophiopogonin D (OP-D), Ginsenoside Rg1 (Rg1), and Ginsenoside Rg3 (Rg3) have individual anti-fibrotic potential, while their synergistic effects in IPF remain to be elucidated. This study aimed to explore how OP-D-Rg1-Rg3 attenuates IPF and to clarify its possible molecular mechanisms. Bleomycin (BLM)-induced cellular senescence and transforming growth factor-β1 (TGF-β1) induce epithelial-mesenchymal transition (EMT) in A549 cells. MTT assay and RSM determined the optimal combination ratio. Cellular senescence and EMT were assessed by SA-β-Gal staining, RT-qPCR, WB, and ELISA. An IPF mouse model was established by intratracheal BLM administration, followed by treatment with the optimized OP-D-Rg1-Rg3 combination, pirfenidone (PFD), or saline for 21 days. Pulmonary structural alterations and molecular changes were then evaluated by micro-CT, HE, Masson, and molecular analyses. The results showed that the synergistic OP-D-Rg1-Rg3 combination markedly attenuated A549 cell senescence, as evidenced by reduced SA-β-Gal activity and decreased expression of p53, p21, p16, and TGF-β1-induced EMT (upregulated E-cadherin, downregulated vimentin, fibronectin, Col-I). In vivo, the combination alleviated AEC2s senescence and pulmonary EMT, improved mouse body weight and lung morphology, reduced histopathological damage, and attenuated IPF. In conclusion, the OP-D-Rg1-Rg3 combination ameliorates IPF by inhibiting AEC2s senescence and EMT, highlighting promising clinical application prospects for IPF treatment.

Cardiac fibrosis is a pivotal pathological process driving adverse cardiac remodeling and a defining feature of end-stage heart disease. Nicotine, a principal constituent of tobacco products, is now recognized as an independent risk factor for cardiovascular disease. However, its direct effects on cardiac fibroblasts (CFs) biology and the molecular mechanisms underlying nicotine-induced cardiac fibrosis remain incompletely understood. Primary CFs and a rat model of nicotine exposure were used to access the pro-fibrotic effects of nicotine. Drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) were employed to identify the cellular targets of nicotine. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP) and quantitative real-time PCR (qRT-PCR) were used to quantify m⁶A modification and microRNA biogenesis. miR-125b-5p overexpression or inhibition, heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1, abbreviated as A2B1 in all figures) silencing, and pharmacological inhibition with cinacalcet HCl were performed both in vitro and in vivo to evaluate the impact of this signaling axis on nicotine-induced fibrotic phenotypes. Collagen deposition, CFs proliferation, and activated transforming growth factor-β1 (TGF-β1)/Mitogen-Activated Protein Kinase (MAPK) signaling were assessed by histology, immunoblotting, and immunofluorescence. Nicotine promoted CFs proliferation and migration, myofibroblasts (MFs) transformation, and collagen accumulation. HNRNPA2B1 was identified as a potential binding target of nicotine. Mechanistically, nicotine up-regulated methyltransferase-like 14 (METTL14), thereby increasing m⁶A methylation of pri-miR-125b. HNRNPA2B1 recognized methylated pri-miR-125b, facilitated its interaction with DiGeorge Syndrome Critical Region 8 (DGCR8), and thereby accelerated miR-125b-5p maturation. Elevated miR-125b-5p suppressed p53 and activated the TGF-β1/MAPK axis, driving cardiac fibrosis. Knockdown of HNRNPA2B1 or treatment with cinacalcet HCl markedly reduced the levels of miR-125b-5p and ameliorated nicotine-induced cardiac fibrosis in vitro and in vivo. Nicotine induces excessive maturation of miR-125b-5p through an m⁶A-dependent, HNRNPA2B1-mediated mechanism, thereby promoting cardiac fibrosis. Targeting this signaling pathway—either genetically or pharmacologically with cinacalcet HCl—effectively attenuates fibrotic remodeling, providing a novel mechanistic rationale and potential therapeutic strategy management of cardiac fibrosis.

To mitigate bacterial infections in aquaculture caused by antibiotic overuse, two highly effective antimicrobial peptides, AS-CATH4 and ALFPm3, were introduced into turbot aquaculture in this study. A microalgal chloroplast expression system was established in Tetraselmis subcordiformis through tandem expression of these two exogenous antimicrobial peptides. This system was then used to produce microalgal feed for turbot (Scophthalmus maximus L.). The in vitro antimicrobial capacity and in vivo functional effects on turbot were evaluated. The results indicated that the engineered microalgal strain (ASD) containing the two antimicrobial peptides stably expressed these peptides and exhibited inhibitory effects against Staphylococcus aureus, Vibrio parahaemolyticus, and V. splendens. Feeding turbot with commercial feed mixed with ASD downregulated inflammatory factors such as TNF-α, IL-1β, and IL-8R in the gut and liver of turbot, thereby modulating inflammatory responses. Simultaneously, this treatment modulated the dynamic equilibrium of the gut microbiota by remodeling the abundance and diversity of gut bacteria. In conclusion, this study provides strong evidence for the use of microalgae oral delivery systems to deliver antimicrobial peptides, thereby enhancing the immunity of aquatic organisms and regulating the function of their gut microbiota.