Editorial: Regulated Cell Death (RCD) in Cancer -Signaling Pathways Activated by Natural Products and Their Nanoformulations

Immacolata Faraone¹Rocchina Miglionico^1*Daniela Russo²

• ¹Department of Health Sciences, University of Basilicata, Potenza, Italy
• ²Department of Health Sciences, University of Basilicata, Universita degli Studi della Basilicata, Potenza, Italy

Cancer remains one of the most significant threats to global health, characterized by high morbidity, mortality, and escalating economic costs (Filho et al., 2025). One of the most promising strategies for cancer treatment is the induction of regulated cell death (RCD), a genetically programmed and tightly controlled process involving a network of signaling pathways (Peng et al., 2022). While apoptosis is the most established and well-characterized form of RCD (Mustafa et al., 2024), increasing resistance to apoptotic signals in tumors has necessitated the exploration of alternative RCD mechanisms, such as ferroptosis, necroptosis, autophagy-dependent cell death, and paraptosis (Tong et al., 2022;Hadian & Stockwell, 2023).The focus of current cancer research is shifting toward combination therapies that can simultaneously target multiple forms of RCD, thus reduce the likelihood of resistance and improve treatment efficacy.In this context, natural products, bioactive compounds derived from plants, fungi, and other organisms, have gained significant attention for their ability to modulate various RCD pathways.Compounds such as alkaloids, flavonoids, terpenoids, and saponins have shown strong therapeutic potential across diverse cancer types (Chen et al., 2023).A range of recent studies have provided compelling evidence for the therapeutic efficacy of natural products in modulating regulated cell death across different cancer types. robustly induce autophagic cell death via endoplasmic reticulum (ER) stress triggered autophagy pathways. Concurrently, metabolomic profiling reveals that both ginsenosides significantly alter the choline-phosphatidylcholine metabolic axis, suggesting that disruption of lipid metabolism contributes to their cytotoxicity. This dual action-activating autophagic cell death while modulating membrane lipid metabolism, provides new insight into NSCLC suppression by ginsenosides. Despite these promising attributes, the poor physicochemical properties of many natural compounds, such as low solubility, instability, and poor oral bioavailability, remain a major challenge. To overcome these limitations, nanotechnology has emerged as a powerful platform to enhance drug solubility, protect active ingredients from degradation, improve cellular uptake, and allow targeted delivery to tumor tissues (Andreani et al., 2024).Pandey et al. summarized the activity of bergenin, a natural isocoumarin with broad-spectrum anticancer effects in cervical, liver, lung, and prostate cancers. Bergenin exerts its effects through reactive oxygen species (ROS) production, DNA damage, and mitochondrial dysfunction, while modulating several signaling pathways, including PI3K/AKT/mTOR, STAT3, and NF-κB. It upregulates pro-apoptotic proteins such as Bax and caspase-3, and downregulates the anti-apoptotic Bcl-2, thus shifting the cell toward apoptotic death. Due to its poor gastrointestinal absorption and low bioavailability, bergenin has been formulated into nanostructured lipid carriers, phospholipid complexes, and silver nanoparticles, significantly enhancing its delivery and anticancer efficacy. The research presented in this Topic underscores the rich potential of natural products to activate various regulated cell death pathways, offering new therapeutic angles for cancers that are resistant to conventional treatments. Furthermore, nanotechnology-based formulations address longstanding issues of poor drug solubility and systemic delivery, advancing these bioactive compounds toward clinical relevance. Continued interdisciplinary efforts integrating natural product chemistry, cancer biology, and drug delivery science are essential for developing next-generation anticancer therapies rooted in nature. This integrated approach not only promises more effective and targeted treatments but also fosters innovation in overcoming drug resistance and improving patient outcomes.