The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

Ferroptosis: mechanisms, biology and role in disease.

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications

Beyond pathogens: microbiota interactions with the plant immune system

Phytohormones play vital roles in the growth and development of plants as well as in interactions of plants with microbes such as endophytic fungi. The endophytic root-colonizing fungus Piriformospora indica promotes plant growth and performance, increases resistance of colonized plants to pathogens, insects and abiotic stress. Here, we discuss the roles of the phytohormones (auxins, cytokinin, gibberellins, abscisic acid, ethylene, salicylic acid, jasmonates, and brassinosteroids) in the interaction of P. indica with higher plant species, and compare available data with those from other (beneficial) microorganisms interacting with roots. Crosstalks between different hormones in balancing the plant responses to microbial signals is an emerging topic in current research. Furthermore, phytohormones play crucial roles in systemic signal propagation as well as interplant communication. P. indica interferes with plant hormone synthesis and signaling to stimulate growth, flowering time, differentiation and local and systemic immune responses. Plants adjust their hormone levels in the roots in response to the microbes to control colonization and fungal propagation. The available information on the roles of phytohormones in beneficial root-microbe interactions opens new questions of how P. indica manipulates the plant hormone metabolism to promote the benefits for both partners in the symbiosis.

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Role of Phytohormones in Piriformospora indica-Induced Growth Promotion and Stress Tolerance in Plants: More Questions Than Answers.

Water, a necessary component of cell protoplasm, plays an essential role in supporting life on Earth; nevertheless, extreme changes in climatic conditions limit water availability, causing numerous issues, such as the current water-scarce regimes in many regions of the biome. This review aims to collect data from various published studies in the literature to understand and critically analyze plants’ morphological, growth, yield, and physio-biochemical responses to drought stress and their potential to modulate and nullify the damaging effects of drought stress via activating natural physiological and biochemical mechanisms. In addition, the review described current breakthroughs in understanding how plant hormones influence drought stress responses and phytohormonal interaction through signaling under water stress regimes. The information for this review was systematically gathered from different global search engines and the scientific literature databases Science Direct, including Google Scholar, Web of Science, related studies, published books, and articles. Drought stress is a significant obstacle to meeting food demand for the world’s constantly growing population. Plants cope with stress regimes through changes to cellular osmotic potential, water potential, and activation of natural defense systems in the form of antioxidant enzymes and accumulation of osmolytes including proteins, proline, glycine betaine, phenolic compounds, and soluble sugars. Phytohormones modulate developmental processes and signaling networks, which aid in acclimating plants to biotic and abiotic challenges and, consequently, their survival. Significant progress has been made for jasmonates, salicylic acid, and ethylene in identifying important components and understanding their roles in plant responses to abiotic stress. Other plant hormones, such as abscisic acid, auxin, gibberellic acid, brassinosteroids, and peptide hormones, have been linked to plant defense signaling pathways in various ways.

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Plants’ Physio-Biochemical and Phyto-Hormonal Responses to Alleviate the Adverse Effects of Drought Stress: A Comprehensive Review

Ferroptosis, an iron-dependent cell death process, was found to occur in Magnaporthe oryzae, and plays a key role in infection-related development therein. Ferroptosis in the rice-blast fungus was confirmed based on five basic criteria. We confirmed the dependence of ferroptosis on ferric ions, and optimized ratio-fluorescence imaging of C11-BODIPY581/591 as a precise sensor for lipid peroxides that mediate ferroptosis in M. oryzae. We uncovered an important regulatory function for reduced glutathione and NADPH oxidases in modulating the superoxide moieties required for ferroptotic cell death. We found ferroptosis to be necessary for the developmental cell death of conidia during appressorium maturation in rice blast. Such ferroptotic cell death initiated first in the terminal cell and progressed sequentially to the entire conidium. Iron chelation or chemical inhibition of ferroptosis caused conidial cells to remain viable, and led to strong defects in host invasion by M. oryzae. Ferroptosis induction exclusively in the host severely constrained the invasive growth of M. oryzae. We found inter-reliant and independent roles for ferroptosis and autophagy in controlling such precise cell death in M. oryzae during pathogenic differentiation. Our study provides significant molecular insights into the role of developmental cell death and iron homeostasis in fungal pathogenesis.

https://nph.onlinelibrary.wiley.com/doi/epdf/10.1111/nph.16636

Ferroptosis contributes to developmental cell death in rice blast.

Fungal effectors at the crossroads of phytohormone signaling.

The cAMP-Protein Kinase A signaling, anchored on CpkA, is necessary for appressorium development and host penetration, but indispensable for infectious growth in Magnaporthe oryzae. In this study, we identified and characterized the gene encoding the second catalytic subunit, CPK2, whose expression was found to be lower compared to CPKA at various stages of pathogenic growth in M. oryzae. Deletion of CPK2 caused no alterations in vegetative growth, conidiation, appressorium formation, or pathogenicity. Surprisingly, the cpkAΔcpk2Δ double deletion strain displayed significant reduction in growth rate and conidiation compared to the single deletion mutants. Interestingly, loss of CPKA and CPK2 resulted in morphogenetic defects in germ tubes (with curled/wavy and serpentine growth pattern) on hydrophobic surfaces, and a complete failure to produce appressoria therein, thus suggesting an important role for CPK2-mediated cAMP-PKA in surface sensing and response pathway. CPKA promoter-driven expression of CPK2 partially suppressed the defects in host penetration and pathogenicity in the cpkAΔ. Such ectopic CPK2 expressing strain successfully penetrated the rice leaves, but was unable to produce proper secondary invasive hyphae, thus underscoring the importance of CpkA in growth and differentiation in planta. The Cpk2-GFP localized to the nuclei and cytoplasmic vesicles in conidia and germ tubes. The Cpk2-GFP colocalized with CpkA-mCherry on vesicles in the cytosol, but such overlap was not evident in the nuclei. Our studies indicate that CpkA and Cpk2 share overlapping functions, but also play distinct roles during pathogenesis-associated signaling and morphogenesis in the rice blast fungus.

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Cpk2, a Catalytic Subunit of Cyclic AMP-PKA, Regulates Growth and Pathogenesis in Rice Blast.

Flavonoids are polyphenolic secondary metabolites that function as signaling molecules, allopathic compounds, phytoalexins, detoxifying agents and antimicrobial defensive compounds in plants. Blast caused by the fungus Magnaporthe oryzae is a serious disease affecting rice cultivation. In this study, we revealed that a natural flavonoid, tangeretin, substantially delays the formation of M. oryzae appressoria and blocks the development of blast lesions on rice plants. Our data suggest that tangeretin has antioxidant activity that interferes with conidial cell death/ferroptosis, which is critical for M. oryzae pathogenicity. Tangeretin showed a comparable inhibition capacity and efficacy to those of the well-established ferroptosis inhibitor liproxstatin-1. Furthermore, overexpression of the NADPH oxidases NOX1 or NOX2 significantly decreased sensitivity towards tangeretin treatment, suggesting Nox-mediated lipid peroxidation as a possible target for tangeretin in regulating redox signaling and ferroptosis in M. oryzae. Our nursery and field tests showed that application of tangeretin can effectively mitigate overall disease symptoms and prevent leaf blast. Our study reveals the plant-derived fungal ferroptosis inhibitor tangeretin as a potential and novel antifungal agrochemical for the sustainable prevention of the devastating blast disease in important cereal crops. This article is protected by copyright. All rights reserved.

Tangeretin inhibits fungal ferroptosis to suppress rice blast.

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Qing Shen

Papers

Ferroptosis contributes to developmental cell death in rice blast.

Fungal effectors at the crossroads of phytohormone signaling.

Cpk2, a Catalytic Subunit of Cyclic AMP-PKA, Regulates Growth and Pathogenesis in Rice Blast.

Tangeretin inhibits fungal ferroptosis to suppress rice blast.

Ferroptosis and microbial pathogenesis.