Ferroptosis: Opportunities and Challenges in Treating Endometrial Cancer.

Further studies are needed on the association of ferroptosis with initiation, metastasis, recurrence, treatment, and prognosis of endometrial cancer. A focus is to be placed on the identification of the key ferroptosis-associated genes in endometrial cancer. Much importance is to be attached to the underlying mechanism of ferroptosis-associated genes in the initiation and progress of endometrial cancer, with the laboratory-derived research results shifting to the clinical investigations to determine proper ferroptosis inducers and precise dose and duration of administration. In so doing, the best treatment plan, either as combination chemotherapy or non-chemotherapy, can be developed for the patient with endometrial cancer.

A large amount of evidence suggest that ferroptosis is involved in all aspects of endometrial cancer, including initiation, metastasis, recurrence, treatment, and prognosis. Ferroptosis-associated gene-based molecular typing model has shown a comparable prognosis predictive value than others, and many conventional drugs, which activate ferroptosis, have also shown favorable antitumor effects in vitro . Targeting ferroptosis has displayed a favorable role in reversing drug resistance of endometrial cancer. Therefore, it is hypothesized that targeting ferroptosis can be an underlying therapeutic approach to endometrial cancer, although the evidence is not sufficient enough at present.

It is well recognized that the prognosis of endometrial cancer is related to quite a number of contributing factors such as tumor histological type, tumor stage, pathological stage, metabolism, and recurrence, which is also true of many ferroptosis-associated genes in endometrial cancer ( Figure 3 ). The high expressions of CDKN1A, SLC7A11, and SAT1 were found to be linked to the low stage, grade of pTNM, and longer survival time in endometrial cancer ( Qin et al., 2021 ). As a ferroptosis suppressor, it was revealed that FANCD2 overexpression was associated with high tumor grade, advanced tumor stage, and lympho-vascular invasion in type I endometrial cancer ( Mhawech-Fauceglia et al., 2014 ), while in type II endometrial cancer, the patients with the positive expression of FANCD2 were found to be more likely to recur within 5 years and with poor 5-year recurrence free survival (RFS) (71.4 vs. 85.5%) and OS (68 vs. 80.3%) ( Mhawech-Fauceglia et al., 2014 ). The expression of HSPA5 was reported to be higher in high-risk endometrial cancer than in low-risk endometrial cancer and normal endometrium, which suggested that HSPA5 was also associated with higher malignant degree and poor prognosis of endometrial cancer ( Teng et al., 2013 ). In addition, univariate and multivariate regression analyses indicated that the high expression of MGST1 was associated with the high clinical stage (TNM), poor primary therapy outcome, poor histological type, high tumor invasion, and poor histologic grade ( Yan et al., 2022 ), hence MGST1 is regarded as a progress predictive factor for endometrial cancer. Association of ferroptosis-associated genes with clinical characteristics of endometrial cancer. As indicated in the graph, there exists an association of ferroptosis-associated genes with the stage, grade, invasion, recurrence, histopathological type, and therapy outcome of endometrial cancer, blue represents the negative and red represents the positive. Moreover, many other ferroptosis-associated genes were also found to be associated with prognosis of endometrial cancer via clinical observation or bioinformatics analysis ( Figure 4 ). A pan-cancer analysis indicated that SLC7A11, a key gene of ferroptosis, was a risk factor for worsen OS in such cancers as adrenocortical carcinoma, bladder urothelial carcinoma, head-and-neck squamous cell carcinoma, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, and skin cutaneous melanoma, while it was a protective factor for prolonged OS for ovarian cancer and rectum adenocarcinoma ( He et al., 2021 ). No association has been reported of SLC7A11 with endometrial cancer; however, the association of SLC7A11 with the prognosis of endometrial cancer remains controversial. Qin et al. (2021 ) reported that SLC7A11 was associated with prolonged survival time of endometrial cancer, which suggested a protective factor. While CDKN1A was found to be an activator of ferroptosis, which was significantly associated with better prognosis of endometrial cancer ( Yamawaki et al., 2017 ); and ACSL4 was associated with lipid metabolism and lipid peroxidation dependent ferroptosis, while the low expression of ACSL4 was observed in endometrial cancer to be associated with better prognosis ( Yu et al., 2022 ). Ferroptosis-associated gene-based protective factor and risk factor in endometrial cancer. A list is made of ferroptosis-associated genes involved in endometrial cancer prognosis based on the previous literature; those which are positively associated with a good prognosis are defined as protective factors, and those which are negatively associated are defined as risk factors. Intriguingly, quite a few research studies have probed into the regulated mechanism of ferroptosis-associated genes in endometrial cancer, as indicated by the evidence that ferroptosis-associated genes were positively related to M1 macrophages, M2 macrophages, T cell follicular helper, and B cells naive, while they were negatively related to NK cells activated, T cells regulatory (Tregs) and neutrophils ( Liu W. et al., 2021 ); and that damage-associated molecular patterns (DAMPS) released by ferroptosis were sensed by the immune cells, thus enhancing inflammatory responses and improving the immune microenvironment in cancer was found ( López-Janeiro et al., 2021 ). Therefore, it was thought that different patients with endometrial cancer could have different immune microenvironments to have different prognosis ( Blaisdell et al., 2015 ; Antomarchi et al., 2019 ; Pan et al., 2019 ). An abnormal microenvironment induced by ferroptosis-associated genes can be the underlying mechanism of poor prognosis in endometrial cancer. In fact, gene-combined panels have been used to predict the prognosis of endometrial cancer. Of them, TCGA molecular typing and ProMisE molecular typing, based on POLE gene, p53 gene, and DNA mismatch repair genes, are the most classic molecular typing of endometrial cancer ( Levine et al., 2013 ; Eriksson et al., 2021 ). Definitely, these molecular typings established play an important role in predicting prognosis and guiding clinical practice; however, two of them still have shortcomings, which limits their clinical application: complicated testing processes and high testing cost, and their consistency with clinical practice still needs to be improved. Therefore, it is significant that a novel, simple, and economical molecular prognostic model be explored in predicting endometrial cancer. It is well known that abnormal ferroptosis is an important reason behind the poor prognosis of endometrial cancer, as indicated by the evidence that molecular typing based on ferroptosis-associated genes showed good prognosis predictive value: 1) the ferroptosis score, based on thirteen ferroptosis-associated genes, was established, and OS of patients with a low score of ferroptosis was superior to that of those with high score of ferroptosis (AUC = 0.726) ( Wang et al., 2021b ); 2) a molecular typing of endometrial cancer, based on six ferroptosis-associated genes of HMOX1, KEAP1, HSBP1, SAT1, CISD1, and GPX4, showed good 1-, 3-, and 5-year prognostic predictive value (AUC = 0.705, 0.676, and 0.713) ( Liu J. et al., 2021 ); 3) a ferroptosis-associated gene signature with eight genes of MDM2, GPX4, PRKAA2, PRNP, SLC11A2, ATP5MC3, PHKG2, and ACO1, showed better 1-, 3-, and 5-year prognostic predictive value (AUC = 0.676, 0.797, and 0.826) than the aforementioned two ferroptosis prognosis molecular typings ( Weijiao et al., 2021 ). Ferroptosis prognosis molecular typing possessed a comparable or superior prognosis predictive value when compared with the previous prognosis molecular typings of endometrial cancer ( Table 1 ) ( Tang et al., 2019 ; Yang et al., 2021b ; Coll-de la Rubia et al., 2021 ; Huang S. et al., 2021 ; Lu N. et al., 2021 ; Pang et al., 2021 ; Wang Z. et al., 2021 ). As indicated by the evidence, ferroptosis-associated genes-based molecular typing can be considered as an effective method to predict the prognosis of endometrial cancer. Molecular typing for endometrial cancer. However, most studies on the correlation of ferroptosis-associated genes with the prognosis of endometrial cancer have been conducted based on bioinformatics analysis, lacking large, and multi-center clinical samples for prospective validation. The sensitivity, specificity, and stability of ferroptosis-associated genes-based molecular typing models still merit further investigations. The correlation of ferroptosis-associated genes with immune response, immune infiltration still remains unclear, and the previously reported studies have been performed mostly based on correlation analysis of clinical cases. Whether there is a causal or concomitant correlation between the abnormal expression of ferroptosis-associated genes with the immune response and immune infiltration in endometrial cancer still needs to be verified by a large number of experiments in vivo and in vitro . More importantly, it remains unclear whether the use of ferroptosis inducer will improve the prognosis of endometrial cancer; further research studies are needed in terms of dosage selection, application method, and therapeutic safety and effectiveness.

Endometrial carcinoma is one of the most common gynecological malignancies. In the United States, there were 66,570 new cases in 2021, of which, 12,940 patients died from endometrial cancer ( Siegel et al., 2022 ). Most endometrial cancers are diagnosed at an early stage, and in most cases, the 5-year survival rate was over 80%; however, we must admit that the prognosis of those who have recurrence or distant metastasis was still not optimistic, and that the 5-year survival rate is only 17.8% ( Jeppesen et al., 2016 ; European Comission 2020 ). Many signaling pathways have been considered to be involved in the development of endometrial cancer, such as mitogen activated kinase-like pathway (MAPK), DNA repair process, PI3K-Akt pathway, steroid hormone receptors-associated pathway, WNT pathways, L1 cell adhesion molecule interaction pathway (L1CAM), and ferroptosis pathway ( López-Janeiro et al., 2021 ). Of them, targeting ferroptosis signaling pathway has been considered as a new therapeutic strategy for the treatment of endometrial cancer. However, it is still unclear how these signaling pathways, especially ferroptosis pathway, modulate the initiation, metastasis, treatment, and prognosis of endometrial cancer. Ferroptosis, a new and iron-dependent cell death form, is different from apoptosis, autophagy, and necrosis. Mainly, ferroptosis plays an important role in amino acid metabolism, oxidative stress, and iron metabolism, which is involved in various physiological and pathological processes, such as neuronal degeneration, antiviral immune response, ischemia re-perfusion injury, and especially in tumor suppression ( Chen et al., 2021a ; Hoy et al., 2021 ; Xiong et al., 2021 ; Lei et al., 2022 ). Studies have found that ferroptosis is closely associated with liver cancer, stomach cancer, pancreatic cancer, breast cancer, stomach cancer, and ovarian cancer ( Wang et al., 2021a ; Jiang et al., 2021 ; Lin et al., 2021 ; López-Janeiro et al., 2021 ; Yang L et al., 2021 ; Yuan Y. et al., 2021 ). Ferroptosis activation has been considered to be a new approach to most tumors ( Eling et al., 2015 ; Sun et al., 2016 ; Roh et al., 2017 ; Zhou et al., 2019 ; Gao et al., 2020 ). In particular, a growing number of studies have focused on the relationship between ferroptosis and endometrial cancer in recent years. Up to now, a large number of studies on ferroptosis in vivo and in vitro have provided new insights into the initiation, metastasis, recurrence, treatment, and prognosis of endometrial cancer. In the current review, we systematically explored the relationship between ferroptosis and the initiation, metastasis, recurrence, treatment, and prognosis of endometrial cancer, in order to provide evidence-based guidance for the diagnosis and treatment of endometrial cancer.