Editorial: Modulation of Ferroptosis via Metabolic and Signaling Pathways: Therapeutic Opportunities Across Malignancies and Degenerative Diseases

Alessandra Fiore^1*Jian Chen^2,3,4*Adriano Martimbianco De Assis^5*

• ¹Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Verona, Italy
• ²Institute of Vascular Anomalies, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
• ³Anhui Province Rural Revitalization Collaborative Technical Service Center, Huangshan University, Huangshan, China
• ⁴Department of Public Health, International College, Krirk University, Bangkok, Thailand
• ⁵Graduate Program in Health and Behaviour, Center of Health Science, Universidade Católica de Pelotas—UCPel, Pelotas, Brazil

Cancer cells often reprogram iron metabolism to support their high proliferative needs (Brown et al. 2020). This makes them particularly sensitive to ferroptotic stress. The study by Zhang et al. in this collection demonstrates this principle in diffuse large B-cell lymphoma. They identify the iron-sulfur protein CISD2 as a regulator of ferroptosis and ferritinophagy, showing that its overexpression reduces chemosensitivity, while its inhibition restores drug responsiveness through ferroptosis induction. Importantly, silencing CISD2 not only promoted ferroptosis but also re-sensitized drugresistant cells to doxorubicin, highlighting ferroptosis as a potential strategy to overcome therapy resistance. This work resonates with a broader trend in oncology: the recognition that ferroptosis can bypass traditional apoptosis-based resistance mechanisms. Alongside GPX4 and system Xc⁻, CISD2 now joins the growing list of ferroptosis regulators that could be exploited therapeutically. If ferroptosis induction is advantageous in cancer, the opposite is true in acute injuries of the nervous system and the heart, where excessive ferroptosis drives cell loss. In the context of spinal cord injury, Tao et al. show that tetramethylpyrazine (TMP), a compound extracted from Ligusticum wallichii, protects neurons by activating the NRF2-ARE pathway. This reduces lipid peroxidation, iron overload, and mitochondrial dysfunction, thereby improving functional recovery. The findings underscore ferroptosis as a major mechanism of neuronal death after trauma and highlight NRF2 activation as a promising neuroprotective approach. Similarly, in myocardial ischemia-reperfusion injury, another major cause of global morbidity, ferroptosis has emerged as a key pathogenic mechanism. Work by Liu et al. on the enzyme SAT1 shows that its upregulation activates the MAPK/ERK pathway and triggers ferroptotic cell death, worsening ischemic injury. Inhibiting SAT1, conversely, alleviates ferroptosis and protects cardiomyocytes, suggesting a novel cardioprotective strategy. These contributions exemplify how ferroptosis inhibition may complement established neuro-and cardioprotective therapies, offering new hope for conditions where therapeutic options remain limited. Beyond cancer and acute injury, ferroptosis also contributes to chronic fibrotic and inflammatory disorders. In pulmonary fibrosis, Chen et al. demonstrate that the traditional herbal formula Gui-Zhi-Fu-Ling-Wan (GFW) alleviates bleomycin-induced lung damage by inhibiting both epithelialmesenchymal transition and ferroptosis. This finding reinforces the idea that ferroptosis is not merely a bystander in fibrosis but an active driver of tissue remodelling. In ophthalmology, Hou et al. highlight the role of ferroptosis in dry eye disease. They show that astaxanthin, a naturally occurring carotenoid, protects corneal epithelial cells by activating the SLC7A11/GPX4 axis and enhancing autophagy. In animal models, this intervention preserved ocular surface integrity and reduced oxidative stress. These data add to the growing recognition that ferroptosis underlies several ocular pathologies, opening new therapeutic perspectives in a field where current treatments remain largely symptomatic. Finally, in osteoarthritis, Gong et al. report that Paeonol protects chondrocytes from interleukin-1β-induced ferroptosis via the AMPK/Nrf2/GPX4 pathway. By preserving mitochondrial function and reducing oxidative stress, Paeonol not only prevented chondrocyte death but also attenuated inflammatory responses, offering a disease-modifying potential for osteoarthritis management. Together, these three studies broaden the scope of ferroptosis research to fibrotic, ocular, and musculoskeletal disorders. Their inclusion emphasizes that ferroptosis is not restricted to acute injuries or cancer but plays a pivotal role in chronic, quality-of-life conditions. The six contributions in this Research Topic collectively advance a crucial message: ferroptosis is a unifying paradigm across biomedical sciences. It is increasingly evident that ferroptosis lies at the intersection of iron metabolism, oxidative stress, lipid signalling, and inflammation, processes that are central to the pathogenesis of numerous diseases. By spanning multiple organs and pathologies, this Research Topic highlights the translational versatility of ferroptosis. It demonstrates how the same molecular pathway can be targeted in opposite directions, induced in tumours to trigger cell death, or inhibited in degenerative diseases to preserve tissue integrity. This duality underscores ferroptosis as both a vulnerability and a liability, depending on the biological context. Notably, several contributions explore naturally derived compounds and multi-component formulations, such as TMP, Paeonol, astaxanthin and GFW; these studies delineate signalling pathways that both intersect with and operate independently of canonical ferroptotic mechanisms, including mitophagy, NRF2 signalling, autophagy and inflammatory cascades. This convergence of mechanistic cell biology with natural product pharmacology broadens the therapeutic landscape and underscores the relevance of ferroptosis to translational and integrative medicine. The rapid expansion of ferroptosis research reflects its ability to connect diverse biomedical fields. Moving forward, key challenges include (i) refining robust and clinically actionable biomarkers for ferroptosis and related redox/iron pathways, (ii) identifying and stratifying patient subgroups most likely to benefit from ferroptosis-targeted or ferroptosis-sparing interventions, (iii) deconvoluting and standardizing multi-component preparations to define active constituents and interactions, and (iv) advancing validated preclinical findings toward well-designed clinical trials with harmonized assays and reporting standards. By presenting work across oncology, neurology, cardiology, pulmonology, ophthalmology, and rheumatology, this Research Topic aims to provide a representative and inclusive perspective. In doing so, it not only highlights mechanistic insights but also illustrates the translational promise of ferroptosis as a therapeutic target across diseases.