Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

Mixed lineage kinase domain-like protein (MLKL) emerged as executioner of necroptosis, a RIPK3-dependent form of regulated necrosis. Cell death evasion is one of the hallmarks of cancer. Besides apoptosis, some cancers suppress necroptosis-associated mechanisms by for example epigenetic silencing of RIPK3 expression. Conversely, necroptosiselicited inflammation by cancer cells can fuel tumor growth. Recently, necroptosis-independent functions of MLKL were unraveled in receptor internalization, ligand-receptor degradation, endosomal trafficking, extracellular vesicle formation, autophagy, nuclear functions, axon repair, neutrophil extracellular trap (NET) formation, and inflammasome regulation. Little is known about the precise role of MLKL in cancer and whether some of these functions are involved in cancer development and metastasis. Here, we discuss current knowledge and controversies on MLKL, its structure, necroptosisindependent functions, expression, mutations, and its potential role as a pro-or anti-cancerous factor. Analysis of MLKL expression patterns reveals that MLKL is upregulated by type I/II interferon, conditions of inflammation, and tissue injury. Overall, MLKL may affect cancer development and metastasis through necroptosis-dependent and -independent functions.

Radiotherapy is commonly used as a cytotoxic treatment of a wide variety of tumors. Interestingly, few case reports underlined its potential to induce immune-mediated abscopal effects, resulting in regression of metastases, distant from the irradiated site. These observations are rare, and apparently depend on the dose used, suggesting that dose-related cellular responses may be involved in the distant immunogenic responses. Ionizing radiation (IR) has been reported to elicit immunogenic apoptosis, necroptosis, mitotic catastrophe, and senescence. In order to link a cellular outcome with a particular dose of irradiation, we performed a systematic study in a panel of cell lines on the cellular responses at different doses of X-rays. Remarkably, we observed that all cell lines tested responded in a similar fashion to IR with characteristics of mitotic catastrophe, senescence, lipid peroxidation, and caspase activity. Iron chelators (but not Ferrostatin-1 or vitamin E) could prevent the formation of lipid peroxides and cell death induced by IR, suggesting a crucial role of iron-dependent cell death during high-dose irradiation. We also show that in K-Ras-mutated cells, IR can induce morphological features reminiscent of methuosis, a cell death modality that has been recently described following H-Ras or K-Ras mutation overexpression.