Ferroptosis, as a new form of regulated cell death, plays a dual role in tumorigenesis and antitumor therapy. ACSL4 and GPX4 are vital regulators of ferroptosis, and several studies have revealed the value of ACSL4 and GPX4 serving as predictive and prognostic biomarkers in patients with tumors (19). In clinical practice, radiotherapy plays a crucial role in the treatment of ESCC; however, the prognostic value of ACSL4 and GPX4 in such a setting remains poorly defined.
To the best of our knowledge, this is the first study to explore the predictive and prognostic value of ACSL4 and GPX4 expression in patients with ESCC receiving adjuvant radiotherapy. The Kaplan-Meier survival analysis and multivariate Cox regression analysis revealed that a high ACSL4 expression was an indicator of a longer OS and DFS in patients with ESCC, and ROC analysis verified its predictive role. In addition, the present study indicated that a high GPX4 expression was a potential indicator of an unfavorable DFS in patients with ESCC, although the ROC analysis revealed a limited predictive value. The findings of the present study suggest that ACSL4 and GPX4 may function as biomarkers for the long-term survival of patients with ESCC receiving adjuvant radiotherapy, and may help to identify candidates for further treatment.
ACSL can catalyze fatty acids to form acyl-CoAs, thereby facilitating fatty acid metabolism and membrane modifications. A total of five isoforms of ACSL, including ACSL1, ACSL3, ACSL4, ACSL5 and ACSL6, have different functions in fatty acid metabolism (20). ACSL4, as a sensitive monitor and a vital contributor of ferroptosis, is crucial for ferroptotic cancer cell death. Yuan et al (15) found that ACSL4 protein expression was positively associated with the amount of ferroptosis in tumor cells, and ACSL4 promoted ferroptosis through the production of 5-hydroxyeicosatetraenoic acid. Previous studies have indicated that an elevated expression of ACSL4 is associated with CD8+ T-cell infiltration, and improved immunotherapeutic responses in malignant cancers (21,22). Based on the currently available data, ACSL4 may play different roles in various tissues; the high expression of ACSL4 predicts the poor survival of patients with ovarian, liver and colorectal cancer, whereas the high expression of ACSL4 has been shown to be associated with improved outcomes of patients with brain, breast, bladder and lung cancer (20,22-25). However, the role of ACSL4 protein expression in patients with ESCC has not yet been systematically investigated. The present study revealed that ACSL4 plays a role in patients with ESCC receiving adjuvant radiotherapy.
GPXs belong to a family of phylogenetically related enzymes, and GPX4 is the only GPX that can catalyze the reduction of lipid peroxides in a complex cellular membrane environment (26). The inactivation of GPX4 in cancer cells with a mesenchymal state can lead to lipid peroxide accumulation and final ferroptosis, rendering these cancer cells highly dependent on GPX4 for survival (27,28). A high expression of GPX4 is regarded as a poor prognostic factor in patients with diffuse large B-cell lymphoma and lung adenocarcinoma (29,30). Shishido et al (31) examined the expression of GPX4 in the pathological specimens of 97 patients with ESCC, and the prognostic analyses revealed that the upregulation of GPX4 was a poor prognostic factor. Shi et al (32)found that GPX4 protein expression was significantly associated with the expression of immune cell markers in ESCC. According to the public results, GPX4 may be a key indicator of the prognosis of patients with ESCC; however, its prognostic value in patients with ESCC who have received post-operative radiotherapy has not been reported to date, at least to the best of our knowledge. The present study revealed that GPX4 may play a role in patients with ESCC receiving adjuvant radiotherapy.
These results are consistent with the findings of previous studies. Shishido et al (31) found that GPX4 positivity was significantly associated with tumor invasion depth, vascular and lymphatic involvement, lymph node metastasis, an advanced stage, a worse OS and recurrence-free survival in patients with ESCC who underwent radical esophagectomy. Tian et al (33) observed a notable upregulation of ACSL4 expression and the downregulation of GPX4 expression following antitumor therapy, which suggested that ACSL4 and GPX4 protein expression may exert opposite effects on tumor progression.
ACSL4 and GPX4 may serve as valuable prognostic biomarkers and promising therapeutic targets, and exert key translational effects on the individualized therapy of patients with ESCC. In clinical practice, these patients with a poor prognosis may be selected as candidates for clinical trials for further treatment. Moreover, targeting ferroptosis is potentially a new avenue for antitumor therapy; it is possible to improve the prognosis of patients with ESCC by inducing ferroptosis through the promotion of ACSL4 or the inhibition of GPX4.
There were some limitations to the present study. First, the present study was based on retrospective data, and the sample size was relatively small, which may influence the reliability of the conclusions. Second, the present study focused on two ferroptosis-associated genes to evaluate their predictive and prognostic value in patients with ESCC receiving adjuvant radiotherapy; however, other genes which were not examined, may also participate this signaling pathway; thus, these remain to be explored. Third, The Cancer Genome Atlas dataset analysis and cell tests may be useful for further investigations into the potential roles of ACSL4 and GPX4 in ESCC. The authors aim to integrate more data to validate the current conclusions. In addition, we aim to conduct a retrospective, multicentre study in the future to verify the power of the predictive model, but neoadjuvant chemoradiotherapy is used increasingly widely; the data for patients with ESCC receiving postoperative radiotherapy is difficult to collect, the external validation requires more time.