| Category | Key findings | Best supporting sources |
|---|---|---|
| Identity/domains | **nhr-49** in **Caenorhabditis elegans** encodes **NHR-49**, an HNF4-like nuclear hormone receptor transcription factor functionally compared with mammalian **HNF4α** and **PPARα**; it has canonical DNA-binding and ligand-binding domains, and GOF mutations map to the LBD. | (pqac-00000002, pqac-00000004) |
| Molecular function | Sequence-specific nuclear receptor transcription factor that both activates and represses gene programs controlling fatty-acid metabolism; required for fasting and oxidative-stress transcriptional responses and works with **MDT-15**. Structural modeling supports likely small-molecule interaction via the LBD, but no definitive endogenous ligand is established. | (pqac-00000002, pqac-00000004, pqac-00000006) |
| Partners/cofactors | Validated partners include **MDT-15** as coactivator, **NHR-80** for desaturase gene activation, and **NHR-66** for repressive lipid-remodeling and sphingolipid programs; **NHR-13** also contributes to desaturase regulation without confirmed direct physical interaction. Yeast two-hybrid using NHR-49-LBD recovered **24 independent cDNAs from 13 genes**. | (pqac-00000003, pqac-00000005) |
| Tissue/cellular localization | Broadly expressed in multiple tissues, including **intestine** and **neurons**. Cell-specific rescue places key functions in **URX/AQR/PQR body-cavity neurons** for pathogen avoidance and calcium control, and in **intestine** for proteostasis and stress programs; hypoxia studies also tested rescue in hypodermis, neurons, and muscle. GOF substitutions did not alter measured subcellular localization. | (pqac-00000004, pqac-00000008, pqac-00000011, pqac-00000014) |
| Key pathways/targets | Major outputs include mitochondrial and peroxisomal β-oxidation genes **acs-2, cpt-5, ech-1**; fatty-acid desaturases **fat-5, fat-6, fat-7**; sphingolipid and lipid-remodeling genes; glyoxylate cycle gene **icl-1**; lipid transport genes **lbp-1, lbp-8**; and stress or immune genes including **fmo-2** and **gst-4**. It also supports autophagy-linked hypoxia adaptation and neuronal lipid homeostasis. | (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000006, pqac-00000014) |
| Phenotypes | Loss of **nhr-49** causes high fat, impaired fasting response, shortened lifespan, altered mitochondrial morphology and function, defective pathogen avoidance, and increased sensitivity to oxidative stress, hypoxia, and infection. GOF alleles are functionally distinct and can produce long-, short-, or normal-lifespan outcomes depending on allele. | (pqac-00000000, pqac-00000004, pqac-00000006, pqac-00000008) |
| Recent 2023-2024 developments | **2023:** review consolidates NHR-49 as a core stress-resilience and healthy-aging regulator; glucose-restriction longevity requires non-cell-autonomous **PAQR-2/NHR-49/Δ9-desaturase** signaling. **2024:** NHR-49 and MDT-15 were shown to couple lipid homeostasis to **HSF-1** proteostasis; neuronal NHR-49 in URX/AQR/PQR tunes calcium dynamics and **PA14** avoidance; free long-chain fatty acids were proposed to activate **NHR-49/80** signaling to initiate development. | (pqac-00000002, pqac-00000007, pqac-00000008, pqac-00000011, pqac-00000012) |
| Quantitative data points | **Microarray cutoff:** absolute log2 ratio at least **0.848** and **p ≤ 0.001** for NHR-49-regulated genes. **Oleic acid rescue:** **300 µM** OA improved avoidance and URX calcium kinetics. **Calcium imaging:** trials with max **ΔF/F0 < 300%** were excluded. **Proteostasis:** intestinal NHR-49 activation reduced **Q35 aggregates by 30%** at day 5 adulthood. **Hypoxia:** after **24 h at 0.5% O2**, about **86% WT** embryos reached L4; after **48 h**, about **44% WT** reached L4. Autophagy-pathway perturbations lowered hypoxia survival to **27–44%** versus **79%** EV control. | (pqac-00000000, pqac-00000009, pqac-00000010, pqac-00000011, pqac-00000014, pqac-00000015) |


*Table: This table summarizes verified identity, molecular function, pathways, localization, phenotypes, and recent 2023-2024 findings for C. elegans NHR-49/UniProt O45666. It provides a concise evidence map for functional annotation with supporting citation IDs.*