The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
The literature summarized here is consistent with the UniProt identity provided: human FBXL5 (F-box and leucine-rich repeat protein 5; UniProt Q9UKA1), an F-box/LRR protein containing an N-terminal hemerythrin-like (Hr) domain and functioning as a substrate receptor for an SCF (SKP1–CUL1–F-box) E3 ubiquitin ligase that regulates iron homeostasis by controlling IRP2/IREB2 stability. Domain architecture and SCF interactions are explicitly described and visualized in structural analyses (sicheri2025analysisoffbox pages 4-7, sicheri2025analysisoffbox media b6a989cb).
FBXL5 is best understood as a substrate-adaptor (F-box) protein that confers substrate specificity to an SCF E3 ubiquitin ligase, enabling polyubiquitination and subsequent proteasomal degradation of specific client proteins (notably IRP2/IREB2) in response to iron/oxygen status (cortadellas2023characterizationofnew pages 41-45, chen2026regulationofmitochondrial pages 4-5).
IRP1 and IRP2 are iron regulatory proteins that bind iron-responsive elements (IREs) in target mRNAs to coordinate iron uptake, storage, and utilization. IRP2 does not assemble an Fe–S cluster (in contrast to IRP1’s aconitase/IRP switch) and is regulated mainly by iron-dependent degradation (liang2026thecriticalrole pages 2-3). FBXL5 is a key mediator of that degradation response (liang2026thecriticalrole pages 2-3).
FBXL5 is widely described as an iron- and oxygen-sensitive regulator: its own stability depends on occupancy of metal cofactors, and its stability controls whether IRP2 is degraded (iron replete) or allowed to accumulate (iron deficiency) (jain2026ironregulationredox pages 8-10, liang2026thecriticalrole pages 2-3).
A structural/functional synthesis of FBXL5 describes three major regions: an N-terminal hemerythrin-like (Hr) domain, a central F-box domain, and a C-terminal leucine-rich repeat (LRR) domain (sicheri2025analysisoffbox pages 4-7). The F-box domain provides a SKP1-binding interface, linking FBXL5 to the SCF machinery, while the LRR region mediates key substrate-binding and cofactor-linked regulation (sicheri2025analysisoffbox pages 4-7).
A retrieved figure from a structural analysis visually summarizes this architecture and shows interaction surfaces with SKP1 and IREB2 (IRP2), as well as a diiron center (sicheri2025analysisoffbox media b6a989cb).
Across mechanistic summaries, a consistent model emerges:
A structural analysis adds mechanistic detail: FBXL5 contains an Hr-like N-terminus that binds a diiron metal center under high iron; loss of metal binding under low-iron conditions promotes conformational changes and FBXL5 turnover (sicheri2025analysisoffbox pages 4-7).
Recent literature continues to emphasize oxygen sensitivity in the FBXL5–IRP2 axis. Review-level evidence states that “iron- and oxygen-dependent degradation of IRP2 is mediated by FBXL5 E3 ligase,” and that FBXL5 structural stability is disrupted under iron deficiency, preventing IRP2 degradation (liang2026thecriticalrole pages 2-3).
Mechanistic work cited in 2024 (and discussed in a Molecular Cell 2024 paper’s contextual citations) points to an oxygen-responsive [2Fe–2S] cluster as part of FBXL5-linked sensing (ast2024mettl17isan pages 24-26). A structural/functional synthesis further describes a [2Fe–2S] cluster association tied to the LRR region and IRP2 recruitment (sicheri2025analysisoffbox pages 4-7), and a review summary likewise states that FBXL5 stability depends on both a diiron hemerythrin-like domain and a [2Fe–2S] cluster (jain2026ironregulationredox pages 8-10).
The dominant, repeatedly supported substrate is IRP2 (IREB2) (chen2026regulationofmitochondrial pages 4-5, cortadellas2023characterizationofnew pages 41-45, jain2026ironregulationredox pages 8-10). Interaction with SKP1 as part of SCF complex assembly is supported by structural/interaction summaries (sicheri2025analysisoffbox pages 4-7, sicheri2025analysisoffbox media b6a989cb).
Evidence retrieved here is limited and partly inconsistent across summaries. One review places FBXL5 activity “in the nucleus” while also noting IRP2/IRP1 function in the cytosol as RNA-binding proteins (chen2026regulationofmitochondrial pages 4-5). Other sources discuss the pathway without strong compartment specificity (jain2026ironregulationredox pages 8-10, liang2026thecriticalrole pages 2-3). Thus, based strictly on retrieved evidence, FBXL5 can operate in nuclear-associated contexts, but the full compartment distribution cannot be conclusively resolved from the current evidence set.
A 2023 Journal of Biological Chemistry article on oxygen modulation of iron homeostasis discusses regulation of the IRP system and references FBXL5 in SCF^FBXL5-mediated control of IRP2, including Fe–S/iron-linked sensing concepts (publication date: May 2023; URL: https://doi.org/10.1016/j.jbc.2023.104701) (guo2024novelbiallelicvariants pages 9-9).
A 2024 PNAS paper on cytosolic [2Fe–2S] protein biogenesis explicitly frames FBXL5 as an “iron-sensing protein” with a hemerythrin domain and discusses oxygen-dependent binding behavior in the context of Fe–S biology (publication date: May 2024; URL: https://doi.org/10.1073/pnas.2400740121) (guo2024novelbiallelicvariants pages 9-9).
A 2024 review focuses on Fe–S clusters as regulatory sensors and includes FBXL5 among mammalian proteins whose stability/function is tied to Fe–S chemistry and oxygen sensitivity (publication date: March 2024; URL: https://doi.org/10.3390/inorganics12040101) (guo2024novelbiallelicvariants pages 9-9).
A 2024 Molecular Cell study (focused on METTL17) cites mechanistic work describing FBXL5 regulation via an oxygen-responsive [2Fe–2S] cluster in iron homeostasis (publication date: January 2024; URL: https://doi.org/10.1016/j.molcel.2023.12.016) (ast2024mettl17isan pages 24-26).
A translational study used liver-specific Fbxl5 knockout mice to create an iron overload–induced hepatic ferroptosis model and interrogate injury pathways in ischemia–reperfusion injury (IRI) (matsumoto2025integratedhepaticferroptosis pages 1-5, matsumoto2025integratedhepaticferroptosis pages 8-11). This represents a concrete “implementation” in experimental medicine: FBXL5 loss serves as a lever to elevate intracellular iron and sensitize tissue to ferroptotic injury.
In the same study, the ferroptosis inhibitor ferrostatin-1 (Fer-1) was administered (1 h prior to IRI) and was used to suppress injury readouts in FBXL5 liver-KO mice (matsumoto2025integratedhepaticferroptosis pages 20-23, matsumoto2025integratedhepaticferroptosis pages 11-13). This is an explicit example of pathway-targeted intervention built around iron/ferroptosis mechanisms that are unmasked or exacerbated by altered FBXL5 function.
The study created an integrated hepatic ferroptosis gene signature (iFerroptosis) and applied it to mouse injury models and human liver samples, alongside histochemical iron staining (Perls) and lipid peroxidation markers (e.g., 4-HNE) (matsumoto2025integratedhepaticferroptosis pages 20-23). This constitutes a practical framework for stratifying ferroptosis-associated pathology in liver injury settings.
Review-level sources emphasize that the FBXL5–IRP2 axis constrains excessive intracellular iron and that disruption of this axis can contribute to oxidative stress and ferroptosis-linked pathology (jain2026ironregulationredox pages 8-10, liang2026thecriticalrole pages 2-3). This aligns with mechanistic disease models where IRP2-dependent iron acquisition programs remain inappropriately active when FBXL5 is destabilized.
Open Targets lists FBXL5 disease/trait associations (e.g., neurodegenerative disease and certain syndromic phenotypes) based on linked evidence sets (publication database record; URL not provided in the tool output) (OpenTargets Search: -FBXL5). These associations should be treated as hypothesis-generating and interpreted alongside mechanistic evidence.
In the hepatic ischemia–reperfusion model using liver-specific Fbxl5 knockout mice, reported group sizes include: control sham n=16, control IRI n=15; FBXL5 liver-KO sham n=10, FBXL5 liver-KO IRI n=13, FBXL5 liver-KO IRI + Fer-1 n=6 (matsumoto2025integratedhepaticferroptosis pages 20-23). Outcomes included serum enzymes (AST/ALT/LDH), histology, and lipid peroxidation staining, with reported very strong statistical significance in some comparisons (e.g., ****p < 0.0001 in presented analyses) (matsumoto2025integratedhepaticferroptosis pages 20-23).
The same work analyzed a human liver resection cohort (n=174) and stratified subsets by iron status (n=143 low-iron vs n=31 high-iron) for certain analyses, reporting that elevated serum iron correlated with sustained/delayed post-operative liver damage recovery (matsumoto2025integratedhepaticferroptosis pages 1-5, matsumoto2025integratedhepaticferroptosis pages 20-23).
| Functional role | Molecular mechanism | Key domains/cofactors | Key substrates/interactions | Localization/compartment (if evidenced) | Evidence notes with citations placeholders |
|---|---|---|---|---|---|
| Iron-responsive substrate receptor in SCF E3 ubiquitin ligase | Under iron-replete conditions, FBXL5 is stabilized and recruits IRP2/IREB2 for ubiquitination and proteasomal degradation, thereby suppressing IRP2-dependent iron-starvation responses | F-box domain; leucine-rich repeat (LRR) region; N-terminal hemerythrin-like domain; diiron center; [2Fe-2S] cluster reported in LRR-associated sensing model | IRP2/IREB2 substrate; SKP1 interaction as SCF component | Nucleus explicitly mentioned in one review; broader IRP pathway acts in cytoplasmic iron-response circuitry | Human FBXL5 is described as hemerythrin-like/F-box/LRR and as the substrate-recognition component of SCF targeting IRP2 (sicheri2025analysisoffbox pages 4-7, chen2026regulationofmitochondrial pages 4-5, cortadellas2023characterizationofnew pages 41-45) |
| Iron/oxygen sensor controlling its own stability | Iron binding stabilizes FBXL5; low iron destabilizes FBXL5 and permits IRP2 accumulation; oxygen sensitivity has been linked to an oxygen-responsive Fe-S-based mechanism | Hemerythrin-like diiron-binding module; oxygen-responsive [2Fe-2S] cluster mechanism | Functional coupling to IRP2 turnover | Nuclear mention reported; no stronger consensus localization extracted here | Reviews and cited mechanistic work describe FBXL5 as iron- and oxygen-sensitive, with stability governed by metal cofactor occupancy (ast2024mettl17isan pages 24-26, jain2026ironregulationredox pages 8-10, chen2026regulationofmitochondrial pages 4-5) |
| Structural adapter linking metal sensing to ubiquitin machinery | F-box mediates SCF assembly through SKP1, while substrate-binding surfaces in the LRR/other conserved regions support IREB2 recognition | Central F-box (SKP1-binding hotspot); C-terminal LRR substrate-binding region; hemerythrin-like metal-sensing domain | SKP1; IREB2; diiron center visualized in structural summary | Not specifically assigned by structural summary | Structural analysis and retrieved figure summarize domain architecture and interactions with SKP1 and IREB2 (sicheri2025analysisoffbox pages 4-7, sicheri2025analysisoffbox media b6a989cb) |
Table: This table summarizes the core functional annotation of human FBXL5 (UniProt Q9UKA1) using only evidence established in the conversation. It highlights FBXL5’s role as an iron/oxygen-sensitive SCF substrate receptor for IRP2, the domains/cofactors supporting that function, and the limited localization evidence retrieved.
A figure from a structural analysis illustrates FBXL5’s Hr/F-box/LRR architecture and interaction with SCF component SKP1 and substrate IREB2/IRP2 (sicheri2025analysisoffbox media b6a989cb).
References
(sicheri2025analysisoffbox pages 4-7): Elliot Sicheri, Daniel Mao, Michael Tyers, and Frank Sicheri. Analysis of fbox substrate adapter proteins using proteosync, a program for projection of evolutionary conservation onto protein atomic coordinates. Computational and Structural Biotechnology Journal, 27:4026-4039, Sep 2025. URL: https://doi.org/10.1016/j.csbj.2025.09.012, doi:10.1016/j.csbj.2025.09.012. This article has 0 citations and is from a peer-reviewed journal.
(sicheri2025analysisoffbox media b6a989cb): Elliot Sicheri, Daniel Mao, Michael Tyers, and Frank Sicheri. Analysis of fbox substrate adapter proteins using proteosync, a program for projection of evolutionary conservation onto protein atomic coordinates. Computational and Structural Biotechnology Journal, 27:4026-4039, Sep 2025. URL: https://doi.org/10.1016/j.csbj.2025.09.012, doi:10.1016/j.csbj.2025.09.012. This article has 0 citations and is from a peer-reviewed journal.
(cortadellas2023characterizationofnew pages 41-45): L Romero Cortadellas. Characterization of new mutations in transferrin, dmt1 and sec23b causing rare iron metabolism-related diseases; and the discovery of racgap1 as the gene …. Unknown journal, 2023.
(chen2026regulationofmitochondrial pages 4-5): Xuyang Chen, Saijun Xiao, Ziwei Zhang, Jiapeng Gong, Jiaqi Wu, Jiayi Wu, Liqin Jin, Jianxin Lyu, and Xiaojun Ren. Regulation of mitochondrial iron homeostasis in tumor cells. Molecular Medicine, Feb 2026. URL: https://doi.org/10.1186/s10020-026-01436-1, doi:10.1186/s10020-026-01436-1. This article has 1 citations and is from a peer-reviewed journal.
(liang2026thecriticalrole pages 2-3): Tiantian Liang, Jiasen Xu, Yan Zhu, He Zhao, Xiaoyu Zhai, Qi Wang, Xiaohui Ma, Limei Cui, and Yan Sun. The critical role of iron homeostasis in neurodegenerative diseases. Neural regeneration research, Apr 2026. URL: https://doi.org/10.4103/nrr.nrr-d-24-01382, doi:10.4103/nrr.nrr-d-24-01382. This article has 1 citations and is from a peer-reviewed journal.
(jain2026ironregulationredox pages 8-10): Chesta Jain and Yatrik M. Shah. Iron: regulation, redox homeostasis, and ferroptosis in cancer. Ferroptosis and oxidative stress, Mar 2026. URL: https://doi.org/10.70401/fos.2026.0022, doi:10.70401/fos.2026.0022. This article has 0 citations.
(ast2024mettl17isan pages 24-26): Tslil Ast, Yuzuru Itoh, Shayan Sadre, Jason G. McCoy, Gil Namkoong, Jordan C. Wengrod, Ivan Chicherin, Pallavi R. Joshi, Piotr Kamenski, Daniel L.M. Suess, Alexey Amunts, and Vamsi K. Mootha. Mettl17 is an fe-s cluster checkpoint for mitochondrial translation. Molecular Cell, 84:359-374.e8, Jan 2024. URL: https://doi.org/10.1016/j.molcel.2023.12.016, doi:10.1016/j.molcel.2023.12.016. This article has 54 citations and is from a highest quality peer-reviewed journal.
(guo2024novelbiallelicvariants pages 9-9): Zhenglong Guo, Dawei Huo, Yingying Shao, Wenke Yang, Jinming Wang, Yuwei Zhang, Hai Xiao, Bingtao Hao, and Shixiu Liao. Novel biallelic variants in ireb2 cause an early-onset neurodegenerative disorder in a chinese pedigree. Orphanet Journal of Rare Diseases, Nov 2024. URL: https://doi.org/10.1186/s13023-024-03465-7, doi:10.1186/s13023-024-03465-7. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 1-5): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 8-11): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 20-23): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(matsumoto2025integratedhepaticferroptosis pages 11-13): Takashi Matsumoto, Akihiro Nita, Yohei Kanamori, Ayato Maeda, Noriko Yasuda-Yoshihara, Kosuke Mima, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Yuta Matsuoka, Katsuya Nagaoka, Keiichi I. Nakayama, Yuki Sugiura, Yasuhito Tanaka, Hideo Baba, and Toshiro Moroishi. Integrated hepatic ferroptosis gene signature dictates pathogenic features of ferroptosis. Hepatology Communications, Oct 2025. URL: https://doi.org/10.1101/2024.10.27.620461, doi:10.1101/2024.10.27.620461. This article has 5 citations and is from a peer-reviewed journal.
(OpenTargets Search: -FBXL5): Open Targets Query (-FBXL5, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.