Glutathione peroxidase 4 (GPX4) is canonically viewed as the primary suppressor of ferroptosis, yet its role in the tumor microenvironment (TME) extends far beyond antioxidant catalysis to encompass immuno-metabolic regulation. In this review, we synthesize recent advances in enzymology, immunology, and cancer metabolism to propose a “lipid peroxidation threshold” framework, wherein GPX4 sets cell-type-specific thresholds that determine susceptibility to ferroptosis across tumor cells, CD8⁺ T cells, dendritic cells (DCs), and myeloid populations. We discuss how these thresholds are dynamically adjusted by post-translational modifications, nutrient competition and intercellular feedback loops, resulting in significant spatial heterogeneity between the tumor core and the tumor invasive front. There is a current selectivity paradox in GPX4 inhibitors, as well as resistance through nuclear factor erythroid 2-related factor 2 (Nrf2) and ferroptosis suppressor protein 1 (FSP1) that restricts the efficacy of GPX4 inhibitors as monotherapy. We focus on rational combination approaches: GPX4 modulation with immune checkpoint blockade (ICB), chemotherapy, and targeting myeloid-derived suppressor cells (MDSCs); and the pressing need for predictive biomarkers and single-cell spatial profiling. We conclude that successful clinical translation requires moving beyond indiscriminate GPX4 inhibition toward precision “threshold engineering” that selectively lowers tumor lipid peroxidation thresholds while sparing immune cells.

Non-coding RNAs (ncRNAs) are the biggest class of regulatory molecules in the human genome, which constitute ~98% of total transcripts, and were once considered as “transcriptional noise”. This review will focus on the newly identified functions of non-coding RNAs (ncRNAs) in cancer biology and therapeutic innovations. We review the existing knowledge on microRNAs, long non-coding RNAs, and circular RNAs in the context of their different experimental and computational studies, and we highlight their mechanisms of action in cancer hallmarks such as proliferation and resistance to apoptosis, metastasis, and metabolic reprogramming. We evaluate the translational landscape of ncRNA-based therapeutics by examining clinical trials in progress and completed, delivery methods, and emerging technologies. This review aims to separate fact from fiction and offer a balanced view on the facts, which will help guide future research and clinical development in the field of ncRNA oncology.

Background: Natural products with unique mechanisms remain of great interest because targeted cancer therapies frequently fail due to toxicity or resistance. Cardiac glycosides have demonstrated antitumor activity, but whether their effects involve microRNA regulation remains largely unexplored. This study investigates whether ouabain derived from Strophanthus gratus (Wall. & Hook. ex Benth.) Baill. (SGO) exerts its antitumor effects through miR-145-5p, a known tumor suppressor, using both colorectal and breast cancer models. Methods: We performed transcriptomic profiling in HCT116 colorectal cancer cells treated with SGO, followed by in vitro assays—including cell viability, caspase 3/7 activity, flow cytometry, and colony formation—in HCT116 and MCF-7 breast cancer cells. In vivo efficacy was evaluated using HCT116 xenograft models in BALB/c-nu/nu mice. miR-145-5p gain- and loss-of-function approaches were employed to determine its functional requirement. Results: SGO dose-dependently suppressed proliferation, induced apoptosis, and inhibited colony formation in both colorectal (HCT116) and breast (MCF-7) cancer cells, and significantly upregulated miR-145-5p levels in both cell types. Transcriptomic analysis identified miR-145-5p as a highly differentially expressed miRNA. In HCT116 xenograft models, SGO inhibited tumor growth by approximately 60% and elevated intratumoral miR-145-5p levels. Importantly, inhibition of miR-145-5p significantly attenuated these effects both in vitro and in vivo, establishing that the antitumor activity of SGO depends on the upregulation/activation of miR-145-5p in both cancer types. Conclusions: We have found that SGO inhibits colorectal and breast cancer growth through a miR-145-5p-dependent mechanism, revealing a previously unrecognized regulatory axis for cardiac glycosides. These findings position SGO as a promising candidate for further preclinical studies and suggest that pharmacologic re-expression of miR-145-5p may represent a viable therapeutic strategy in targeted therapy.

Non-coding RNAs (ncRNAs) regulate gene expression at multiple levels in cancer, yet their functional plasticity and the slow pace of clinical translation remain incompletely explained. This review is organized around a unifying theme: ncRNAs act as integrative nodes connecting the epigenetic, transcriptional, signaling, and metabolic regulatory layers. Building on the established signal, sponge, scaffold, and guide archetypes of long non-coding RNA function, we extend this schema into a 4S+G model that adds a splice-regulatory archetype and embeds all five modes in a three-axis taxonomy spanning structural topology, subcellular localization, and molecular mode of operation, thereby capturing context-dependent functions that binary structural categories cannot accommodate. We dissect chromatin remodeling dynamics, evaluate the competing endogenous RNA hypothesis against stoichiometric evidence, and trace metabolic–epigenetic feedback circuits that stabilize malignant states. We then critically appraise the clinical record of ncRNA therapeutics, from the termination of MRX34 to the modest efficacy of subsequent candidates, and analyze the delivery, immunogenicity, and biomarker barriers that distinguish oncology from other indications for RNA drugs. Emerging solutions, including ligand-directed extrahepatic delivery, spatial transcriptomics, and deep learning-based target prediction, are assessed against these bottlenecks. The 4S+G framework links mechanistic understanding to a realistic roadmap for developing ncRNA-targeted cancer therapeutics with favorable risk–benefit profiles.