{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRetinoic acid‐related orphan receptor C (RORC), and in particular its T‐cell specific isoform RORγt, is emerging as a master regulator of immune cell differentiation and function. It is critically required for the differentiation of proinflammatory T helper 17 (Th17) cells – a lineage characterized by interleukin‐17 (IL‐17) production – as well as for the acquisition of specialized features in several other lymphocyte subpopulations. RORC expression drives the transcription of key Th17 genes (such as IL17A, IL17F, IL‐23R, and CCL20) and is rapidly induced by transforming growth factor‐β1, even in the presence of cytokines that divert cells to alternative fates. Moreover, its activity is modulated by counter‐regulatory factors such as Foxp3, explaining a balance between pro‐inflammatory Th17 cells and regulatory T cells. Even in innate lymphoid cells, RORγt marks progenitors that contribute to mucosal immunity and lymphoid tissue organization."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond conventional Th17 differentiation, RORC governs an array of immune functions that impact host defense and inflammatory pathology. It is essential not only in adaptive immunity but also in orchestrating innate immune responses mediated by lymphoid tissue inducer cells and RORγt‐expressing innate lymphoid cells, including natural killer T (iNKT) and γδ T cells. In patients with congenital RORC loss‐of‐function mutations, defective production of IL‐17 by T cells accounts for susceptibility to mucocutaneous candidiasis and mycobacterial disease. In addition, aberrant RORC expression is implicated in inflammatory disorders such as psoriasis, endometriosis, and chronic obstructive pulmonary disease, where an imbalance between IL‐17–mediated inflammation and regulatory signals is evident. Recent studies have also revealed that RORC function is tightly regulated via post‐translational mechanisms—for example by ubiquitination or deubiquitination via factors such as TRAF5, USP4, USP17—and its activity can be pharmacologically modulated by small‐molecule inverse agonists (including ursolic acid and TMP778) as well as by endogenous lipids such as hydroxycholesterols and 7‐oxygenated sterols."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its central role in immune regulation, RORC functions in non‐immune as well as tumor‐related contexts. In several cancers such as bladder, breast, gastric, and melanoma, altered RORC (and its isoforms) expression is linked to modulation of cell proliferation, metabolic reprogramming, epithelial–mesenchymal transition, and chemoresistance. RORC has been shown to negatively regulate oncogenic signaling cascades (for instance the transforming growth factor‐β/EMT axis) while promoting DNA repair, and its activity is influenced by ligand binding—by both classical (vitamin D metabolites) and non‐calcemic derivatives—and by nuclear receptor coactivators. In some settings, RORC activity maintains a favorable clinical outcome, as seen in estrogen receptor–positive breast cancers and prostate malignancies, and its variable expression may serve as a valuable therapeutic target or prognostic marker. Moreover, RORC-dependent transcriptional programs can be modulated through interactions with other transcription factors (such as Ahr, Foxp3, and c‐Maf) to affect homing receptor expression and the balance between inflammatory and regulatory cell phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Astar Winoto, Dan R Littman "}, {"type": "b", "children": [{"type": "t", "text": "Nuclear hormone receptors in T lymphocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0092-8674(02)00710-9"}], "href": "https://doi.org/10.1016/s0092-8674(02"}, {"type": "t", "text": "00710-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11983153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11983153"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhaofeng Huang, Huimin Xie, Ruiqing Wang, et al. 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