Ferroptosis is a regulated, specific type of cell death that is iron-dependent and has unchecked lipid peroxidation and oxidative stress, making it distinct from apoptosis and necrosis. First described by Dixon et al., (2012), ferroptosis was characterized as a nonapoptotic, iron-dependent death induced by the small molecule Erastin, which blocks System Xc⁻, cystine-glutamate antiporter (Maet al., 2021). Ferroptosis has since picked up steam as an oncology and neurodegenerative disease target for drugs because it has a two-pronged role: to induce it to kill cancer cells and to block it to rescue neurons (Liet al., 2020).

Molecularly, ferroptosis results from a dysbalance between antioxidant defence mechanisms and oxidative stress. Glutathione Peroxidase 4 (GPX4) is a chief regulator that protects against ferroptosis by lipid peroxide reduction. Inhibition or diminution of Glutathione, its cofactor, triggers ferroptotic death. System Xc⁻ plays a critical role in the import of cystine required for glutathione production; inhibition by Erastin or Sorafenib triggers glutathione deficiency and ROS accumulation (Huet al., 2019). Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) helps by PUFA-enriching membrane, making it susceptible to peroxidation. Opposing the pathway, Ferroptosis Suppressor Protein 1 (FSP1) and Coenzyme Q10 (CoQ10) block ferroptosis and sustain redox equilibrium (Konget al., 2019).

Ferroptosis is especially useful in cancer therapy for drug resistance breaking in apoptosis-resistant cancers like Glio Blastoma Multiforme (GBM), Hepato Cellular Carcinoma (HCC), Pancreatic Ductal Adeno Carcinoma (PDAC), and Triple-Negative Breast Cancer (TNBC) (Zhanget al., 2019). Compounds like Erastin, RSL3, Sorafenib, and FIN56 have been shown to induce ferroptosis by inhibiting antioxidant pathways and iron homeostasis. RSL3 directly inhibits GPX4, whereas Sorafenib inhibits System Xc⁻. Such agents may be combined with chemotherapy or immune checkpoint inhibitors to increase cancer cells’ therapeutic effect and immune clearance (Chang, 2016).

Conversely, in neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), and Amyotrophic Lateral Sclerosis (ALS), ferroptosis inhibition is a therapeutic target (Zhuet al., 2020). Neurons, highly susceptible to oxidative damage by PUFA-rich membranes and high oxygen use, are especially vulnerable to iron-mediated ferroptotic injury. Inhibitors Ferrostatin-1 and Liproxstatin-1 block oxidative damage, and iron chelators such as Deferoxamine block limiting neurotoxicity. Excess iron in the substantia nigra in PD and lipid peroxidation in AD and HD have been demonstrated to support ferroptosis contribution to these diseases (Nassar and Blanpain, 2016).

Ferroptosis also crosstalks with apoptosis, necroptosis, and autophagy. Although apoptosis is caspase-dependent, ferroptosis provides a caspase-independent mechanism for apoptosis-resistant tumour cell death. Autophagy can induce ferroptosis by breaking down ferritin and GPX4, promoting lipid peroxidation and iron release, but it can also be protective by alleviating oxidative stress through mitophagy (Katoh, 2017).

Despite the therapeutic potential, ferroptosis is confronted with clinical hurdles such as an absence of certified biomarkers, drug selectivity, and delivery issues, especially across the blood-brain barrier. Future studies must address identifying valid biomarkers, enhancing nanoparticle-mediated delivery systems, and investigating immune system interactions. Finally, ferroptosis possesses revolutionary potential in oncology and neurology, dependent on interdisciplinarity to move research into practice (Reyaet al., 2001).

Ferroptosis has gained increasing attention in oncology because it is implicated in iron-dependent lipid peroxidation. Wang et al., (2021) outlined its mechanisms and identified Erastin and RSL3 as targets of resistant cancer cells. Yang et al., (2020) explored the reversal of cancer stem cell resistance. Shen et al., (2018) identified combining ferroptosis with immunotherapy. Sun et al., (2023) highlighted reducing toxicity. Lu et al., (2018) and Tong et al., (2022) discussed its crosstalk with other death pathways. These findings are shown in Table 1.

A comprehensive search in PubMed, Scopus, and Web of Science for articles published over the past ten years from 2015 to 2024 with keywords like ferroptosis, cancer therapy, neurodegeneration, lipid peroxidation, and oxidative stress was conducted.

Peer-reviewed original research, clinical trials, and extensive preclinical studies were searched with a focus on reporting mechanisms, modulators, and therapeutic uses.

Key findings were compiled regarding regulatory pathways, drug targets, efficacy, toxicity, and limitations.

Data were analyzed for trends, gaps, and strategies in cancer and neurodegeneration to provide an evidence-based overview of ferroptosis for clinical translation.

Ferroptosis, an iron-dependent form of programmed cell death, is a promising target for cancer therapy due to its ability to induce death in chemotherapy-resistant cancer cells (Zhaoet al., 2020). It is triggered by lipid peroxide excess, primarily by inhibiting Glutathione Peroxidase 4 (GPX4) or System Xc⁻, a cystine-glutamate antiporter. GPX4 inhibitors RSL3 and ML162 interfere with antioxidant defences, while Erastin and Sorafenib inhibit System Xc⁻, glutathione depletion, and ROS excess (Nieet al., 2022). These mechanisms make cancers such as Triple-Negative Breast Cancer (TNBC), Hepato Cellular Carcinoma (HCC), and Glioblastoma (GBM) ferroptosis-vulnerable. Combination with chemotherapy, radiotherapy, or immunotherapy enhances therapeutic efficacy (Lu et al., 2018). Radiotherapy enhances iron availability, and immune checkpoint inhibitors increase immune-mediated clearance. Tumour cells resist ferroptosis by antioxidant overexpression or FSP1 upregulation (Jianget al., 2020). Strategies such as co-inhibition of GPX4 and FSP1, combination therapy, and nanoparticle drug delivery are being investigated to bypass resistance and selectively kill tumour cells with reduced toxicity (Leiet al., 2020), as illustrated in Table 2.

Ferroptosis is a major contributor to neurodegenerative diseases like Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD) due to its link with oxidative stress and iron dysregulation. Lipid metabolism-dependent neurons are especially susceptible to ferroptosis-induced cell death by iron overload and lipid peroxidation. Elevated iron in the substantia nigra (PD) and cortex (AD) and lipid peroxidation products like malondialdehyde and 4-hydroxynonenal in postmortem brain tissue reflect ferroptosis contribution to neuronal loss (Milleret al., 2020). Inhibition of ferroptosis has been recognized as an exciting neuroprotective strategy. Lipid peroxidation, oxidative stress inhibitors like Ferrostatin-1 and Liproxstatin-1, and iron chelators like Deferoxamine inhibit iron-induced damage and neuronal damage. New studies explore cerebrospinal fluid and blood-based ferroptosis biomarkers, but challenges remain in discovering blood-brain barrier–permeable inhibitors that preserve normal iron homeostasis. Additional studies are required to translate these results into effective neurotherapeutics (Degterevet al., 2005).

Pharmacological modulation of ferroptosis has also been an effective cancer therapy and neuroprotection strategy. Ferroptosis inducers Erastin, RSL3, Sorafenib, and FIN56 inhibit System Xc⁻ or directly inhibit GPX4, resulting in lethal lipid peroxidation (Jianget al., 2021). These are especially effective against apoptosis-resistant cancer. Inhibitors Ferrostatin-1, Liproxstatin-1, and Vitamin E, however, inhibit lipid peroxidation and exhibit neuroprotection in models of Alzheimer’s and Parkinson’s disease. This bimodal modulation characterizes ferroptosis as a drug and a disease-preventive target (Hsiehet al., 2021). Clinical use is, however, hindered by off-target toxicity, low bioavailability, and low specificity. Inducers damage normal tissue, whereas inhibitors disrupt iron homeostasis. Drug delivery is another challenge, especially across the blood-brain barrier (Koeberleet al., 2023). Overcoming these challenges, research focuses on nanoparticle-based drug delivery systems, stable ferroptosis biomarkers, and best combination regimens. These are needed to safely and effectively translate ferroptosis-targeting drugs to clinical use (Consoliet al., 2024), as illustrated in Table 3.

Ferroptosis has extensive crosstalk with other controlled cell death pathways, including apoptosis, necroptosis, and autophagy, to form a highly interconnected network that controls disease progression and therapeutic response (Leeet al., 2018). Different from caspase-dependent apoptosis, ferroptosis is triggered by iron loading and lipid peroxidation. However, ferroptosis serves as a backup cell death pathway in cancer cells with inhibited apoptosis, e.g., with TP53 mutations (Chenet al., 2024). Necroptosis, regulated by RIPK1 and MLKL, shares overlapping oxidative stress features with ferroptosis, and one can replace the other under some tumour conditions. Autophagy has a bifunctional role in the regulation of ferroptosis: it triggers ferroptosis by degrading GPX4 and ferritin, making more iron available, but suppresses ferroptosis by mitophagy, reducing oxidative stress (Wuet al., 2023). Suppression of autophagy may thus enhance the induction of ferroptosis in tumours. Such interactions illustrate the therapeutic potential of combination regimens co-targeting ferroptosis and apoptosis or autophagy pathways, particularly in therapy-resistant tumours (Renet al., 2021; Wuet al., 2024). Such interaction is provided in Table 4.

Significant translational constraints hamper ferroptosis studies in clinic application. A lack of disease monitoring and patient stratification through ferroptosis-specific biomarkers is the biggest issue since current markers, such as lipid peroxidation and iron level, are non-ferroptosis-specific (Weiland et al., 2019). Drug specificity is also a problem, with inducers of ferroptosis having the risk of targeting healthy tissues to provoke toxicity, particularly in tissues high in polyunsaturated fatty acids. Tumour heterogeneity necessitates personalized medicine, and the blood-brain barrier limits ferroptosis-targeting drugs’ effectiveness in neurodegenerative diseases such as Alzheimer’s and Parkinson’s (Alim et al., 2019).

Ferroptosis is an iron-mediated, regulated type of cell death defined by lipid peroxidation and oxidative damage, differentiating it from apoptosis and necrosis. Therapeutic uses are currently the subject of intense scrutiny, especially in cancer and neurodegenerative diseases. Resistance mechanisms, regulation, and translational barriers must be better understood to create practical clinical applications (Zille et al., 2017).

In cancer, ferroptosis offers a solution against apoptosis-insensitive tumours such as Hepato Cellular Carcinoma (HCC), Glio Blastoma Multiforme (GBM), and Triple-Negative Breast Cancer (TNBC). Therapies such as RSL3, ML162, Erastin, and Sorafenib block Glutathione Peroxidase 4 (GPX4) or interfere with the cystine-glutamate antiporter System Xc⁻, depleting Glutathione and lipid peroxidation and resulting in ferroptosis (Han et al., 2020). Induction of ferroptosis with inducers in combination with chemotherapy, radiotherapy, or immunotherapy is synergistic. Radiotherapy, for example, enhances the iron levels in tumours, sensitizing them to ferroptosis, and immune checkpoint blockade enables immune-mediated ferroptotic cell clearance (Bebber et al., 2020). Resistance in cancer cells is attained through Ferroptosis Suppressor Protein 1 (FSP1) upregulation, NRF2 antioxidant response, and heat shock protein activation. Blocking these mechanisms must be attained to optimise ferroptosis-based therapy (Kayagakiet al., 2011).

Ferroptosis enhances neuronal degeneration in neurodegenerative disorders due to the brain’s high oxygen requirement, Polyunsaturated Fatty Acid (PUFA), and iron content. Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Huntington’s Disease (HD) have been linked to ferroptosis by iron overload and lipid peroxidation markers such as Malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE) in damaged brain areas (Kayagakiet al., 2013). Neuroprotectants such as Ferrostatin-1, Liproxstatin-1 and iron chelators such as Deferoxamine inhibit ferroptosis by inhibiting lipid peroxidation and oxidative stress. Their therapeutic use is, however, hampered by poor ability to penetrate the Blood-Brain Barrier (BBB) and disruption of systemic iron homeostasis (Shiet al., 2014). Moreover, the absence of ferroptosis-specific biomarkers makes early diagnosis and monitoring difficult, and the development of BBB-permeable inhibitors and sensitive biomarkers is recommended (Wanget al., 2017).

Pharmacological modulation of ferroptosis has progressed with attempts to optimize inducers and inhibitors. Although drugs such as Erastin, RSL3, and FIN56 are promising in cancer, inhibitors Ferrostatin-1 and Liproxstatin-1 are neuroprotective (Rogerset al., 2019). Nevertheless, off-target toxicity is still problematic, particularly for non-neoplastic cells with high PUFA content. This emphasizes the need for improved drug selectivity and bioavailability. Nanoparticle-based delivery systems are being explored to enhance the specificity and minimize systemic exposure of ferroptosis-targeting therapies, including crossing BBB barriers (Liuet al., 2019).

Elucidation of how ferroptosis intersects with other cell death mechanisms, such as apoptosis, necroptosis, and autophagy, can yield clues for combination therapy. Autophagy can inhibit or induce ferroptosis by modulating ROS and GPX4 degradation, thus holding the potential for multi-targeted therapy (Ruanet al., 2018). In addition, the translation of ferroptosis-based therapies into the clinic needs the establishment of accurate diagnosis tools. Existing biomarkers such as lipid peroxidation and iron metabolism markers are non-specific, and thus, non-invasive imaging or blood-based biomarkers are urgently needed. Tumour heterogeneity is also challenging since varied cancers are differentially sensitive to ferroptosis. Personalized medicine through metabolic profiling is needed to optimise patient outcomes (Liuet al., 2016).

Future studies on ferroptosis will require focusing on improving drug specificity, reducing toxicity, and targeted delivery, primarily through nanoparticle-based systems. Combination therapy, for instance, of ferroptosis inducers with immunotherapy or apoptosis-targeting therapeutics may enhance efficacy in resistant cancers. In neurodegeneration, the discovery of ferroptosis inhibitors that can cross the blood-brain barrier is critical for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. A critical area of progress is the discovery of ferroptosis-specific biomarkers for diagnosis, patient selection, and treatment monitoring. Elucidation of ferroptosis interactions with the immune system and cancer microenvironment may also lead to better immunotherapeutic strategies. Interdisciplinary collaborations between pharmacology, oncology, and neuroscience are critical for translation to the clinic.

Ferroptosis is a paradigm shift for anticancer and neurodegenerative disease therapeutic strategies. Iron-catalyzed and lipid peroxidation-driven is a new mechanism of apoptosis-resistant cancer cell killing, while inhibition can save neurons from death. Agents like Erastin, Sorafenib, and RSL3 are of anticancer interest, while Ferrostatin-1 and Liproxstatin-1 can provide neuroprotection. There are, however, obstacles to its therapeutic use, such as off-target toxicity, delivery constraints, and lack of effective biomarkers. Precision medicine, combination therapy, and advanced delivery systems are the key to the complete clinical potential of ferroptosis, with opportunities for more effective, specific, and personalized therapy.

The authors thank the researchers whose work has contributed to understanding ferroptosis in disease treatment and institutions and colleagues who made access to the relevant literature possible.