Exploring a 7-gene prognostic model based on ferroptosis for efficiently guiding immunotherapy in melanoma patients

PurposeAlthough skin cutaneous melanoma (SKCM) is a relatively immunotherapy-sensitive tumor type, there is still a certain fraction that benefits less from treatment. Ferroptosis has been demonstrated to modulate tumor progression in many cancer types. This study focused on ferroptosis-related genes to construct a prognostic model for SKCM patients.Materials and methodsGene expression profiles of SKCM samples were obtained from public databases. Unsupervised consensus clustering was used to determine molecular subtypes related to ferroptosis. Least absolute shrinkage and selection operator (LASSO) and stepwise Akaike information criterion (stepAIC) were applied to construct a prognostic model based on differentially expressed genes between two molecular subtypes.ResultsC1 and C2 subtypes were identified with differential prognosis and immune infiltration. A 7-gene prognostic model was constructed to classify samples into high-FPRS and low-FPRS groups. Low-FPRS group with favorable prognosis had higher immune infiltration and more enriched immune-related pathways than the high-FPRS group. The two groups showed distinct sensitivity to immunotherapy, with the low-FPRS group predicted to have more positive response to immunotherapy than the high-FPRS group. A nomogram based on the FPRS score and clinical features was built for more convenient use.ConclusionsThe critical role of ferroptosis involved in SKCM development was further validated in this study. The prognostic model was efficient and stable to be applied in clinical conditions to support clinicians in determining personalized therapy for SKCM patients especially those with metastasis.     

靶向铁死亡的癌症疗法

铁死亡是一种铁依赖性的,由脂质活性氧累积所引发的调节性细胞死亡方式。铁死亡的启动和执行取决于铁稳态、脂质代谢和抗氧化系统的交集。基于对铁死亡与癌症相关信号通路之间交互作用的深入了解,已设计和开发了一系列诱导癌细胞铁死亡的试剂,包括实验性化合物、临床药物和纳米材料。本文综述了铁死亡的调节机制和靶向铁死亡的癌症疗法。     

Iron homeostasis in arthropathies: From pathogenesis to therapeutic potential

Iron is an essential element for proper functioning of cells within mammalian organ systems; in particular, iron homeostasis is critical for joint health. Excess iron can induce oxidative stress damage, associated with the pathogenesis of iron-storage and ageing-related diseases. Therefore, iron levels in body tissues and cells must be tightly regulated. In the past decades, excess iron content within joints has been found in some patients with joint diseases including hemophilic arthropathy, hemochromatosis arthropathy, and osteoarthritis (OA). Currently, increased evidence has shown that iron accumulation is closely associated with multiple pathological changes of these arthropathies. This review summarizes system-level and intracellular regulation of iron homeostasis, and emphasizes the role of iron in synovial alterations, cartilage degeneration, and subchondral bone of several arthropathies. Of note, we discuss the potential link between iron homeostasis and OA pathogenesis. Finally, we discuss the therapeutic potential of maintaining iron homeostasis in these arthropathies.     

铁死亡与重大慢性疾病

铁死亡是近年发现的一种铁依赖的新型细胞死亡方式,其特征是脂质过氧化物和活性氧簇的过量蓄积。大量研究表明,铁死亡不仅在重大慢性疾病的发生发展过程中发挥重要作用,而且在不同的疾病背景下扮演不同角色。目前认为,铁死亡可抑制肿瘤生长并增加多种肿瘤对化疗药物和免疫治疗的敏感性,因此诱导铁死亡的发生拓展了肿瘤治疗思路。然而,在心脑血管疾病和神经退行性疾病中,铁死亡的发生通过引发正常组织器官损伤和功能丧失直接参与疾病的发生、发展及转归,因此针对心脑血管疾病和神经退行性疾病,抑制铁死亡的发生能够有效预防并延缓这些疾病的发生和发展。本文综述了铁死亡在恶性肿瘤、神经退行性疾病和心脑血管疾病三类不同重大慢性疾病中的最新研究进展及其潜在的作用机制,系统讨论了靶向铁死亡在防治重大慢性疾病中的临床应用前景,为重大慢性疾病的防治提供新的依据。     

铁死亡与重大慢性疾病

铁死亡是近年发现的一种铁依赖的新型细胞死亡方式，其特征是脂质过氧化物和活性氧簇的过量蓄积。大量研究表明，铁死亡不仅在重大慢性疾病的发生发展过程中发挥重要作用，而且在不同的疾病背景下扮演不同角色。目前认为，铁死亡可抑制肿瘤生长并增加多种肿瘤对化疗药物和免疫治疗的敏感性，因此诱导铁死亡的发生拓展了肿瘤治疗思路。然而，在心脑血管疾病和神经退行性疾病中，铁死亡的发生通过引发正常组织器官损伤和功能丧失直接参与疾病的发生、发展及转归，因此针对心脑血管疾病和神经退行性疾病，抑制铁死亡的发生能够有效预防并延缓这些疾病的发生和发展。本文综述了铁死亡在恶性肿瘤、神经退行性疾病和心脑血管疾病三类不同重大慢性疾病中的最新研究进展及其潜在的作用机制，系统讨论了靶向铁死亡在防治重大慢性疾病中的临床应用前景，为重大慢性疾病的防治提供新的依据。     

脊髓损伤“气滞血瘀”病机理论与铁死亡的关系

“气滞血瘀”是脊髓损伤重要的中医病机理论,其科学内涵有待进一步阐释。铁死亡作为脊髓损伤重要的病理,其分子生物学和病理学或许与“气滞血瘀”病机理论有密切相关性。从铁死亡的调控机制入手,揭示活血化瘀中药治疗脊髓损伤的分子机制,为中医药治疗脊髓损伤提供分子生物学依据,丰富中医药现代化的研究思路和手段。     

铁死亡相关机制与子宫内膜癌

子宫内膜癌是女性生殖系统三大恶性肿瘤之一,严重危害女性健康。近年研究发现,铁死亡在子宫内膜癌的发生、发展中起到重要作用。作为一种细胞程序性死亡方式,铁死亡与铁代谢、脂质代谢和氧化应激等生物过程密切相关。研究发现通过调控子宫内膜癌细胞铁代谢及氧化应激,可以促进癌细胞铁死亡,抑制肿瘤细胞增殖,且调控铁死亡的相关通路可以影响子宫内膜癌患者化疗敏感性,分析铁死亡相关基因表达可以预测子宫内膜癌患者预后。因此,铁死亡通路相关蛋白有望成为子宫内膜癌治疗新靶点。综述铁死亡的发生机制及其在子宫内膜癌的发生、治疗中的作用,并分析铁死亡相关分子作为一种新型的分子分型预测子宫内膜癌预后的潜在应用价值,为铁死亡在子宫内膜癌治疗领域中的应用提供新思路。     

IFNγ signaling integrity in colorectal cancer immunity and immunotherapy

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade (ICB). The interferon gamma (IFNγ) signaling pathway drives spontaneous and ICB-induced antitumor immunity. In this review, we summarize recent advances in the epigenetic, genetic, and functional integrity of the IFNγ signaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB. Moreover, we discuss how to target IFNγ signaling to inform novel clinical trials to treat patients with colorectal cancer.     

针刺调控铁死亡治疗脑卒中的信号通路研究进展

脑卒中的发病机制是一个动态演变过程,表现为一系列神经毒性和神经保护相互作用的反应,参与反应的蛋白质作为信号通路通常在外界刺激下激活。目前已明确针刺能通过抑制脑卒中后脑组织神经细胞铁死亡从而促进神经功能修复,近年来针刺通过调控铁死亡治疗脑卒中的相关信号通路研究取得了显著进展,主要包括以下几方面：miR-23a-3p和核转录因子红系2样2(NFE2L2)信号通路;p62/Kelch样ECH关联蛋白1/核因子E2相关因子2(p62/Keap1/Nrf2)信号通路;α7nAChR介导的Janus激酶2/信号转导及转录激活因子3(JAK2/STAT3)信号通路;环磷酸腺苷/cAMP依赖性蛋白激酶/cAMP反应元件结合蛋白(cAMP/PKA/CREB)信号通路;磷脂酰肌醇-3激酶/蛋白激酶B(PI3K/AKT)信号通路;p38丝裂原活化蛋白激酶(MAPK)信号通路;过氧化物酶体增殖物激活受体γ辅激活因子1α/线粒体转录因子A(PGC-1α/TFAM)信号通路;Notch信号通路和脑源性神经营养因子(BDNF)介导的Nrf2信号通路。其中有已被证实的信号通路,亦有待研究的信号通路。     

铁自噬及相关基因NCOA4、FTH1在口腔鳞癌中的研究进展

铁自噬(ferritinophagy)是一种与铁死亡关系密切的自噬类型,由核受体共激活因子4 (nuclear receptor coativator 4,NCOA4)介导铁蛋白在自噬溶酶体中降解,然后使铁蛋白结合的铁降解释放出游离铁,是铁代谢的重要途径。近年来,越来越多的研究表明,铁自噬和铁死亡在肿瘤发生发展中起着重要作用。但目前铁自噬在口腔鳞癌中的作用机制尚未完全阐明,对口腔鳞癌中铁自噬机制的深入研究,有望帮助寻找此类疾病治疗的新靶点。本文对铁自噬在口腔鳞癌中作用研究的最新进展作一综述。