Squamous cell carcinoma (SCC) remains a significant health concern with increasing incidence rates globally. Recent advances in cancer biology have highlighted ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, as a potential therapeutic avenue. However, many cancer cells develop resistance mechanisms to ferroptosis, limiting treatment efficacy. This paper examines recent discoveries regarding the role of aldehyde dehydrogenase 3A1 (ALDH3A1) in mediating ferroptosis resistance in SCC. Research demonstrates that ALDH3A1, regulated by the TP63 oncogene, functions as an antioxidant shield that protects SCC cells from ferroptotic cell death. Importantly, pharmaceutical inhibition of ALDH3A1 sensitizes SCC cells to ferroptosis inducers, suggesting a promising combination therapy approach. These findings contribute to our understanding of SCC pathophysiology and highlight ALDH3A1 as both a potential biomarker and therapeutic target for improved SCC treatment strategies.
Squamous cell carcinoma (SCC) is the second most common type of skin cancer, with an increasing worldwide incidence over the past two decades (Coudray et al., 2025). While most cutaneous SCCs have a good prognosis, a subset of tumors is associated with poor outcomes, including local recurrence, nodal metastasis, distant metastasis, and disease-specific death (Coudray et al., 2025). It is estimated that approximately 10,000 patients die annually from cutaneous SCC in the United States alone, highlighting the need for improved treatment approaches (Coudray et al., 2025).
Traditional treatment methods for SCC include surgical excision, radiation therapy, and in advanced cases, systemic therapies (ASCO Post, 2025). However, patients who develop SCC are at increased risk of developing multiple new lesions over time, making prevention and effective treatment crucial aspects of care (News-Medical, 2025). Recent advances in cancer biology have identified ferroptosis, a unique type of iron-dependent programmed cell death characterized by the accumulation of lipid peroxides, as a potential therapeutic strategy for various cancers, including SCC.
Ferroptosis differs from other forms of programmed cell death, such as apoptosis and necroptosis, in its biochemical mechanisms and morphological features. It is triggered by the accumulation of iron and the oxidation of lipids in cell membranes (Jiang et al., 2025). While ferroptosis is considered a natural defense mechanism to eliminate damaged or unhealthy cells, many cancer cells develop resistance to ferroptosis, enabling their survival and proliferation.
This paper focuses on recent discoveries regarding the role of aldehyde dehydrogenase 3A1 (ALDH3A1) in mediating ferroptosis resistance in SCC. Understanding the mechanisms of ferroptosis resistance in SCC could potentially lead to the development of new therapeutic strategies that overcome this resistance and improve treatment outcomes for patients with this common and potentially deadly form of cancer.
The research team led by Professor JIANG Yanyi from the Hefei Institutes of Physical Science of the Chinese Academy of Sciences employed a comprehensive methodology to investigate the role of ALDH3A1 in ferroptosis resistance in SCC (Jiang et al., 2025). Their experimental approach included:
This multifaceted approach allowed the researchers to comprehensively investigate the role of ALDH3A1 in ferroptosis resistance in SCC and to evaluate the potential therapeutic implications of targeting this mechanism.
The research conducted by Jiang et al. (2025) demonstrated that ALDH3A1, an enzyme known for its role in detoxifying harmful substances in the body, is significantly overexpressed in SCC cells compared to normal cells. This overexpression was consistently observed across patient samples and various SCC cell lines, suggesting a common mechanism in SCC pathophysiology.
Through a series of experimental manipulations, the researchers established that ALDH3A1 functions as an "antioxidant shield" in SCC cells. This enzyme effectively neutralizes toxic compounds that would normally cause lipid peroxidation and subsequent ferroptotic cell death. The protective mechanism appears to be particularly related to the enzyme's ability to prevent the accumulation of lipid peroxides, which are key drivers of ferroptosis.
When ALDH3A1 levels were reduced in SCC cells through genetic knockdown approaches, the cells exhibited increased sensitivity to ferroptosis inducers. This finding confirmed the protective role of ALDH3A1 against ferroptotic cell death in SCC cells.
Further investigations revealed that TP63, a known oncogene, acts as a "master switch" for ALDH3A1 expression in SCC cells. The research demonstrated that TP63 directly binds to and activates the ALDH3A1 gene, triggering the protective mechanism against ferroptosis.
When TP63 expression was suppressed, SCC cells lost their resistance to ferroptosis. Importantly, this effect could be reversed by reactivating ALDH3A1, confirming the critical role of the TP63-ALDH3A1 axis in ferroptosis resistance in SCC cells.
Perhaps the most clinically relevant finding was that combining EN40, an ALDH3A1 inhibitor, with RSL3, a ferroptosis inducer, had a synergistic effect in both cell culture and animal models. This combination treatment effectively disrupted the cancer cells' defense mechanisms against ferroptosis, making them more vulnerable to this form of cell death.
In 3D organoid systems, which more closely mimic the in vivo tumor environment than traditional cell culture, the combination therapy also demonstrated significant efficacy, further supporting its potential clinical relevance.
The findings presented by Jiang et al. (2025) provide significant insights into the mechanisms of ferroptosis resistance in SCC and highlight potential therapeutic strategies to overcome this resistance. The identification of ALDH3A1 as a key mediator of ferroptosis resistance in SCC represents an important advancement in our understanding of SCC biology and potential treatment approaches.
ALDH3A1 has been previously recognized for its role in the detoxification of aldehydes, which can cause cellular damage through protein adduction and DNA cross-linking (Coudray et al., 2025). The current findings expand our understanding of ALDH3A1's function in cancer cells, particularly its role in protecting against ferroptosis-induced cell death.
The overexpression of ALDH3A1 in SCC likely provides these cancer cells with a survival advantage by enhancing their resistance to oxidative stress, including the lipid peroxidation that drives ferroptosis. This may partially explain why some SCC cells are particularly resilient and difficult to eliminate through conventional treatment approaches.
The identification of TP63 as a transcriptional regulator of ALDH3A1 provides further insights into the molecular pathways that govern ferroptosis resistance in SCC. TP63 is known to play crucial roles in epithelial development and differentiation and has been implicated in various cancers, including SCC (Coudray et al., 2025).
The direct regulation of ALDH3A1 by TP63 establishes a clear oncogenic pathway that promotes ferroptosis resistance in SCC cells. This pathway may represent a specific vulnerability that could be targeted therapeutically, particularly in SCCs with high TP63 expression.
The finding that ALDH3A1 inhibition sensitizes SCC cells to ferroptosis inducers has significant therapeutic implications. This suggests that a combination therapy approach targeting both ALDH3A1 and inducing ferroptosis could be more effective than either approach alone.
Current treatment approaches for SCC primarily focus on surgical removal of tumors and, in some cases, adjuvant radiation or chemotherapy (Demehri et al., 2025). However, for patients with multiple or recurrent lesions, these approaches may be insufficient. The development of targeted therapies that exploit specific vulnerabilities in SCC cells, such as their dependence on ALDH3A1 for ferroptosis resistance, could provide new options for these patients.
Moreover, the identification of ALDH3A1 as a potential biomarker for ferroptosis resistance suggests that it could be used to identify patients who might benefit most from ferroptosis-inducing therapies. This personalized medicine approach could enhance treatment efficacy while minimizing unnecessary treatment for patients unlikely to respond.
It is worth comparing the ALDH3A1-targeting approach with other emerging therapies for SCC. Recent research has shown promising results with immunotherapies that activate the immune system against SCC cells. For example, Demehri et al. (2025) reported that a combination of calcipotriol (a vitamin D analog) and 5-fluorouracil (5-FU) effectively eliminated precancerous lesions and prevented SCC by activating CD4+ T helper cells.
While these immunotherapeutic approaches work by enhancing the body's immune response against cancer cells, the ALDH3A1-targeting approach focuses on disrupting an intrinsic resistance mechanism within the cancer cells themselves. These distinct mechanisms suggest that these approaches might be complementary and could potentially be combined for enhanced efficacy.
While the findings of Jiang et al. (2025) are promising, several limitations and questions remain to be addressed. First, the generalizability of these findings to different subtypes of SCC and to SCCs arising in different anatomical locations needs to be established. Second, the potential side effects of ALDH3A1 inhibition on normal cells, particularly those that may rely on this enzyme for protection against oxidative stress, need to be carefully evaluated.
Future research should focus on:
The research conducted by Jiang et al. (2025) has uncovered a critical mechanism of ferroptosis resistance in SCC, mediated by the enzyme ALDH3A1 under the transcriptional control of TP63. This pathway provides SCC cells with an "antioxidant shield" that protects them from ferroptotic cell death, potentially contributing to their survival and proliferation.
The finding that ALDH3A1 inhibition sensitizes SCC cells to ferroptosis inducers offers a promising therapeutic strategy for SCC treatment. The combination of ALDH3A1 inhibition (e.g., with EN40) and ferroptosis induction (e.g., with RSL3) could potentially overcome a key resistance mechanism in SCC cells and improve treatment outcomes.
Furthermore, ALDH3A1 may serve as a biomarker to identify patients who could benefit from ferroptosis-based therapies, allowing for a more personalized treatment approach. As our understanding of the molecular mechanisms governing ferroptosis resistance in cancer continues to evolve, targeted therapies aimed at these mechanisms may become an important component of the cancer treatment armamentarium.
In conclusion, the identification of ALDH3A1 as a mediator of ferroptosis resistance in SCC represents an important advancement in our understanding of SCC biology and highlights a potential therapeutic vulnerability that could be exploited for improved SCC treatment.
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Jiang, Y., Kong, S., et al. (2025, March 6). ALDH3A1 mediates ferroptosis resistance in squamous cell carcinoma through TP63-dependent antioxidant function. Oncogene. [Note: This is based on the provided information; the actual citation would need the complete author list, volume, and page numbers]
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