Interferons (IFNs) are a family of cytokines that orchestrate a wide range of antiviral, immunoregulatory, and antitumor activities. This review provides a comprehensive overview of the molecular mechanisms underlying IFN signaling, including both canonical JAK (janus kinases)-STAT (signal transducers and activators of transcription) pathways and non-canonical branches such as MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)-AKT (protein kinase B)-mTOR (mechanistic target of rapamycin). The intricate interplay between these signaling modules and transcriptional, epigenetic, and post-transcriptional regulators is essential for maintaining immune homeostasis and tailoring context-dependent immune responses. Under physiological conditions, IFNs are essential for host defense, driving antiviral gene expression, activating innate immune cells, and shaping adaptive immune responses, including T and B cells. Conversely, dysregulation of IFN signaling contributes to the development of autoimmune diseases, neuroinflammation, cardiovascular disorders, and cancer. Tumor cells can exploit IFN-induced suppressive molecules to evade immune attack. The currently emerging therapeutic strategies of IFN signaling have evolved into a dual strategy: replacement therapy in immunodeficient states, and pathway inhibition in autoimmune conditions. Additionally, IFN-based combination therapies with immune checkpoint blockade and radiotherapy have demonstrated synergistic potential but require precise control of dosing and timing to avoid immune exhaustion. Advances in single-cell transcriptomics, proteomics, and metabolomics are providing novel insights into IFN heterogeneity, enabling the development of personalized IFN-based treatments. This review highlights the clinical implications and emerging strategies to harness or restrain IFN signaling for therapeutic benefit.

Statins are associated with gastric cancer (GC) risk. The present study aimed to clarify the efficacy of statins on the overall survival (OS) benefits in patients with GC. Publications were retrieved from PubMed, Embase, and the Cochrane Library as of April 2022. Data from the eligible cohort, case‐control studies, and randomized control trials (RCTs) were extracted for the meta‐analysis. Hazard ratio (HR) and 95% confidence intervals (CI) were used to assess the association between statins users and OS in GC patients. Subgroup analysis was performed based on the study design (prospective vs. retrospective). A total of 6 studies encompassing 5693 GC patients were included. Statins added to the standard treatment prolonged the patient’s OS outcome (HR (95% CI): 0.72 (0.53–0.97), p = 0.032; I² = 88.0%, p_{heterogeneity} < 0.001). A prospective study did not find any statistically significant difference in OS between statins users vs. nonstatin users (HR (95% CI): 0.92 (0.68–1.26), p = 0.614; I² = 11.7%, p_{heterogeneity} = 0.322), whereas the retrospective studies showed prolonged OS in statins users (HR (95% CI): 0.63 (0.42–0.961), p = 0.032; I² = 94.6%, p_{heterogeneity} < 0.001). Statin users had significantly improved OS compared to nonstatin users in GC treatment. This long‐term survival benefit was only observed in the pooled analysis of retrospective studies but not in prospective studies.

Ferroptosis, an iron-dependent form of programmed cell death driven by lipid peroxidation, plays a critical dual role in the pathogenesis and treatment of bone diseases. While it can be therapeutically harnessed to eliminate malignant cells in osteosarcoma, its aberrant activation contributes to the degeneration of bone and cartilage in osteoporosis, osteoarthritis, and intervertebral disc degeneration, thereby severely impairing the intrinsic regenerative and repair capacity of musculoskeletal tissues. A significant challenge is the precise modulation of ferroptosis to concurrently inhibit pathological cell death and activate regenerative and protective processes. This review systematically elucidates the therapeutic potential of natural products in treating these bone diseases by targeting ferroptosis, with a dedicated focus on their emerging role in promoting tissue regeneration and repair. We report that a spectrum of natural compounds, such as icariin, astragaloside IV, and baicalein, not only inhibits ferroptosis in osteoblasts, chondrocytes, and nucleus pulposus cells—exacerbating a cytoprotective effect—but also actively promotes a conducive microenvironment for regeneration. These benefits are mediated through the modulation of key pathways, including the Nrf2/HO-1 axis, glutathione peroxidase 4 restoration, and System Xc ^– , which collectively reduce oxidative stress, restore cellular homeostasis, and enhance the function of bone marrow mesenchymal stem cells and progenitor cells. Despite this promise, key issues persist, including the cell type-specific effects of ferroptosis modulators, the complex crosstalk between ferroptosis and other cell death or inflammatory pathways, and the poor bioavailability of many natural agents. This regenerative potential is closely linked to the resolution of ferroptosis-associated inflammation and oxidative damage, allowing progenitor cells to proliferate and differentiate. In conclusion, targeting ferroptosis with natural products represents a promising regenerative medicine strategy that connects the inhibition of pathological degeneration with the stimulation of bone and cartilage repair. The multi-target and tissue-protective nature of these compounds offer significant clinical potential. Future research should prioritize the development of advanced delivery systems (e.g., nanoparticle-based), the integration of network pharmacology and multi-omics approaches for target discovery, and the validation of these regenerative outcomes in sophisticated 3D disease models and clinical trials.