{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNLRP6 has emerged as a multifaceted regulator of intestinal homeostasis. In the gut, it forms atypical inflammasomes and modulates key signaling pathways such as NF‑κB and MAPK to govern mucus secretion and the production of antimicrobial peptides, thereby maintaining microbial ecology and epithelial barrier integrity. Dysregulated NLRP6 signaling has been implicated in several inflammatory intestinal disorders, including ulcerative colitis and functional dyspepsia, and infections by pathogens like Candida albicans have been shown to inhibit its expression, contributing to compromised barrier function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOutside the gastrointestinal tract, NLRP6 also exerts significant immunomodulatory functions. In periodontal tissues, its down‑regulation has been associated with the inflammatory processes of periodontitis, while in rheumatoid arthritis synovial cells, overexpression of NLRP6 dampens pro‑inflammatory cytokine production and NF‑κB activation via promotion of lysosome‑dependent degradation of signaling intermediates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of tissue remodeling and tumorigenesis, NLRP6 displays context‑dependent roles. In hepatic stellate cells, increased levels of NLRP6 suppress fibrogenic responses by inhibiting TGF‑β1/Smad2/3 signaling, suggesting anti‑fibrotic functions in chronic liver disease. Conversely, in gastric cancer, reduced NLRP6 expression—mediated in part by oncogenic long noncoding RNAs—and its interactions with molecules such as GRP78 have been linked to enhanced tumor cell proliferation, while in glioblastoma, NLRP6 augments PI3K/AKT signaling via destabilization of the p85α subunit, thereby promoting tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also supports roles for NLRP6 in non‐canonical tissues and systemic processes. In the kidney, preliminary studies indicate a potential involvement of NLRP6 in acute kidney injury, while its expression in dental pulp raises the prospect of a role in local immune defense. Moreover, NLRP6 influences systemic iron metabolism by modulating ferroportin‐mediated iron efflux in a NRF2‑dependent manner, and genetic association studies have linked polymorphisms at the NLRP6 locus with male essential hypertension."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditionally, NLRP6 has been implicated in modulating the immune microenvironment in cancer metastasis and systemic inflammatory states such as sepsis. Experimental models of colorectal liver metastasis have demonstrated that the absence of NLRP6 disrupts the accumulation of immunosuppressive myeloid‑derived suppressor cells, potentially altering tumor progression. In sepsis, controversial roles have been reported, with evidence supporting both pro‑ and anti‑inflammatory functions of the NLRP6 inflammasome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Paras K Anand, Thirumala-Devi Kanneganti "}, {"type": "b", "children": [{"type": "t", "text": "NLRP6 in infection and inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Microbes Infect (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.micinf.2013.06.009"}], "href": "https://doi.org/10.1016/j.micinf.2013.06.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23811097"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23811097"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Grace Y Chen "}, {"type": "b", "children": [{"type": "t", "text": "Role of Nlrp6 and Nlrp12 in the maintenance of intestinal homeostasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201344135"}], "href": "https://doi.org/10.1002/eji.201344135"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24338634"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24338634"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Maayan Levy, Hagit Shapiro, Christoph A Thaiss, et al. 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