---
provider: falcon
model: Edison Scientific Literature
cached: false
start_time: '2026-03-06T03:10:18.531103'
end_time: '2026-03-06T03:24:56.689737'
duration_seconds: 878.16
template_file: templates/gene_research_go_focused.md
template_variables:
  organism: human
  gene_id: BIRC6
  gene_symbol: BIRC6
  uniprot_accession: Q9NR09
  protein_description: 'RecName: Full=Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein
    ligase BIRC6 {ECO:0000303|PubMed:36758104, ECO:0000303|PubMed:36758105, ECO:0000303|PubMed:36758106};
    EC=2.3.2.24 {ECO:0000269|PubMed:36758104, ECO:0000269|PubMed:36758105, ECO:0000269|PubMed:36758106};
    AltName: Full=BIR repeat-containing ubiquitin-conjugating enzyme {ECO:0000303|PubMed:14765125};
    Short=BRUCE {ECO:0000303|PubMed:14765125}; AltName: Full=Baculoviral IAP repeat-containing
    protein 6; AltName: Full=Ubiquitin-conjugating BIR domain enzyme apollon {ECO:0000303|PubMed:10544019};
    Short=APOLLON {ECO:0000303|PubMed:10544019};'
  gene_info: Name=BIRC6; Synonyms=KIAA1289;
  organism_full: Homo sapiens (Human).
  protein_family: Belongs to the BIRC6 family.
  protein_domains: BIR_rpt. (IPR001370); BIRC6. (IPR022103); UBQ-conjugat_E2_core.
    (IPR000608); UBQ-conjugating_enzyme/RWD. (IPR016135); BIR (PF00653)
provider_config:
  timeout: 600
  max_retries: 3
  parameters:
    allowed_domains: []
    temperature: 0.1
citation_count: 17
---

## Question

# Gene Research for Functional Annotation

## ⚠️ CRITICAL: Gene/Protein Identification Context

**BEFORE YOU BEGIN RESEARCH:** You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

### Target Gene/Protein Identity (from UniProt):
- **UniProt Accession:** Q9NR09
- **Protein Description:** RecName: Full=Dual E2 ubiquitin-conjugating enzyme/E3 ubiquitin-protein ligase BIRC6 {ECO:0000303|PubMed:36758104, ECO:0000303|PubMed:36758105, ECO:0000303|PubMed:36758106}; EC=2.3.2.24 {ECO:0000269|PubMed:36758104, ECO:0000269|PubMed:36758105, ECO:0000269|PubMed:36758106}; AltName: Full=BIR repeat-containing ubiquitin-conjugating enzyme {ECO:0000303|PubMed:14765125}; Short=BRUCE {ECO:0000303|PubMed:14765125}; AltName: Full=Baculoviral IAP repeat-containing protein 6; AltName: Full=Ubiquitin-conjugating BIR domain enzyme apollon {ECO:0000303|PubMed:10544019}; Short=APOLLON {ECO:0000303|PubMed:10544019};
- **Gene Information:** Name=BIRC6; Synonyms=KIAA1289;
- **Organism (full):** Homo sapiens (Human).
- **Protein Family:** Belongs to the BIRC6 family.
- **Key Domains:** BIR_rpt. (IPR001370); BIRC6. (IPR022103); UBQ-conjugat_E2_core. (IPR000608); UBQ-conjugating_enzyme/RWD. (IPR016135); BIR (PF00653)

### MANDATORY VERIFICATION STEPS:

1. **Check if the gene symbol "BIRC6" matches the protein description above**
2. **Verify the organism is correct:** Homo sapiens (Human).
3. **Check if protein family/domains align with what you find in literature**
4. **If you find literature for a DIFFERENT gene with the same or similar symbol, STOP**

### If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

**DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE.** Instead:
- State clearly: "The gene symbol 'BIRC6' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

### Research Target:

Please provide a comprehensive research report on the gene **BIRC6** (gene ID: BIRC6, UniProt: Q9NR09) in human.

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.

## Output

# Comprehensive Research Report: Human **BIRC6** (BRUCE/Apollon) Functional Annotation

## 0) Identity verification (critical disambiguation)
The requested target is **human BIRC6** (UniProt **Q9NR09**), also known as **BRUCE** and **Apollon**, a very large (~528–530 kDa) inhibitor-of-apoptosis (IAP) family protein containing an N‑terminal **BIR** (baculovirus IAP repeat) domain and a C‑terminal **UBC** (ubiquitin‑conjugating/E2 core) domain, with reported **chimeric E2/E3 ubiquitin‑ligase activity**. This matches the UniProt description provided and is explicitly supported by recent mechanistic literature. (liu2024molecularmechanismsunderlying pages 1-2, US20170015997A1 pages 19-29)

## 1) Key concepts and definitions (current understanding)

### 1.1 Dual E2/E3 ubiquitin enzyme
BIRC6 is unusual among IAP proteins because it is described as functioning both as a ubiquitin **conjugating enzyme (E2)** and a ubiquitin **ligase (E3)**, enabling it to directly catalyze substrate ubiquitylation and thereby modulate protein stability and signaling. (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 7-7)

### 1.2 BIR domain–mediated client binding (apoptosis regulators)
The **BIR domain** is a protein–protein interaction module characteristic of IAPs. In BIRC6, it is described as binding active caspases (including caspase‑3, ‑6, ‑7, and ‑9), providing a mechanistic basis for caspase‑cascade inhibition and apoptosis suppression. (US20170015997A1 pages 19-29)

### 1.3 LC3 and LIR-mediated autophagy interactions
Autophagy involves the ubiquitin‑like modifier LC3/Atg8. BIRC6 contains an **LC3-interacting region (LIR)** motif that mediates association with LC3, connecting BIRC6 to autophagy regulation and to the crosstalk between autophagy and apoptosis. (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 8-9)

## 2) Primary molecular function: reaction catalyzed and substrate specificity

### 2.1 Catalytic activity and reaction context
The core biochemical reaction is **protein ubiquitylation**, i.e., transfer of ubiquitin to lysine residues on substrate proteins through the canonical E1→E2→E3 cascade. In the recent structural/mechanistic work, BIRC6 is presented as both E2/E3 and is found in complexes enriched with the E1 enzyme **UBA6**, consistent with an enzymatically competent ubiquitylation machinery assembled around BIRC6. (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 7-8)

### 2.2 Substrate: LC3 (autophagy)
**LC3 lysine 51 (K51)** is described as the **sole** ubiquitylation site on LC3 in this context, and BIRC6 (together with UBA6) is proposed to catalyze **mono-ubiquitylation** at **LC3 K51**, which suppresses autophagy and biases toward apoptosis. (liu2024molecularmechanismsunderlying pages 7-7)

Functional consequences (cellular readouts) include:
- **LC3 K51R** (non‑ubiquitylatable) inhibits degradation of GFP‑LC3 in chase assays and increases LC3‑II/I ratios under autophagy-inducing conditions, consistent with increased autophagic flux/LC3 accumulation. (liu2024molecularmechanismsunderlying pages 7-7)
- LC3 K51R is also reported to promote autophagic degradation of BIRC6 and p62 and to reduce apoptosis markers (e.g., cleaved caspase‑3) under stress. (liu2024molecularmechanismsunderlying pages 7-7, liu2024molecularmechanismsunderlying pages 7-8)

Independent support (mechanistic follow-on): BIRC6 knockdown reduces ubiquitination of an LC3B mutant (K42R), and a **K42R/K51R** double mutant shows no ubiquitination, supporting K51 as the critical ubiquitination acceptor in that setting. (xu2025neddylationmodificationstabilizes pages 6-7)

### 2.3 Substrate/clients: caspase pathway components and Smac
BIRC6 is described as inhibiting apoptosis by promoting ubiquitylation and degradation of proapoptotic factors (including mature Smac and effector caspases), and it **strongly inhibits caspase‑9 activity** in vitro (while weakly inhibiting caspase‑3), consistent with a primary role at the initiator caspase level. (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 4-5)

### 2.4 Substrate: Axin (Wnt/β-catenin signaling)
In renal cell carcinoma (RCC) models, BIRC6 is reported to interact with **Axin** and promote its **ubiquitination** and **turnover**, activating **Wnt/β‑catenin** signaling. This expands substrate scope from canonical apoptosis/autophagy regulators to a central signaling scaffold controlling β‑catenin. (zhong2024birc6modulatesthe pages 3-5, zhong2024birc6modulatesthe pages 1-2)

## 3) Biological processes and pathway placement

### 3.1 Apoptosis–autophagy balance (2024 mechanistic model)
A major current understanding is that BIRC6 coordinates a balance between apoptosis and autophagy through dual control of:
- **Caspase-9/procaspase-9** availability and activity, and
- **LC3** stability/function via LC3 K51 ubiquitylation.

Autophagy induction (starvation/rapamycin) reduces procaspase‑9 levels and active caspase‑9 in an autophagy‑dependent manner (reversed by bafilomycin A1; Atg5 dependence described), linking autophagy machinery to initiator caspase regulation. (liu2024molecularmechanismsunderlying pages 4-5, liu2024molecularmechanismsunderlying pages 7-8)

A quantitative datum reported is that rapamycin shortens the half‑life of a procaspase‑9 mutant from **~12 h** to **<8 h**. (liu2024molecularmechanismsunderlying pages 4-5)

### 3.2 Wnt/β‑catenin axis in cancer
BIRC6-mediated destabilization of Axin is positioned upstream of β‑catenin accumulation and Wnt/β‑catenin pathway activation, with downstream phenotypes including increased proliferation, migration/invasion, stemness-like properties, and drug resistance (sunitinib) in RCC models. (zhong2024birc6modulatesthe pages 1-2, zhong2024birc6modulatesthe pages 5-8)

## 4) Subcellular localization and molecular complexes

### 4.1 Structural organization and complex architecture (cryo-EM)
A 2024 cryo‑EM structure (3.6 Å) reveals BIRC6 forms an **anti-parallel U‑shaped dimer** with a **central substrate-binding cavity** that accommodates Smac/DIABLO, and includes multiple domains (including a ubiquitin-like domain, N‑terminal WD40 β‑propeller, a small BIR domain, and a UBC domain). (liu2024molecularmechanismsunderlying pages 1-2)

The figure evidence in the paper depicts the U‑shaped dimer and a conceptual model of dimer-dependent exposure/occlusion of the LIR motif that mediates LC3 binding. (liu2024molecularmechanismsunderlying media efc726e5, liu2024molecularmechanismsunderlying media 1e06fe05)

### 4.2 Smac/DIABLO binding and competition logic
Smac binds in the BIRC6 central cavity and in cells can outcompete **caspase‑3** and **HtrA2** for BIRC6 binding, but notably does **not** outcompete **procaspase‑9**, suggesting BIRC6 has hierarchical or spatially distinct client binding modes. (liu2024molecularmechanismsunderlying pages 4-5, liu2024molecularmechanismsunderlying pages 1-2)

### 4.3 Cytoplasmic colocalization with Axin
In RCC cells, BIRC6 and Axin are reported to **colocalize in the cytoplasm**, supporting cytosolic ubiquitination/turnover of Axin as the proximate mechanism for Wnt activation. (zhong2024birc6modulatesthe pages 3-5)

## 5) Recent developments and latest research (prioritizing 2023–2024)

### 5.1 2024 Nature Communications: structural mechanism, Smac-binding cavity, LC3-binding model
Key 2024 advances include a resolved structural model of BIRC6 dimerization and Smac occupancy, plus mechanistic dissection of how BIRC6 engages LC3 via a LIR motif and how dimerization may gate LIR accessibility (“closed/open” model). (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 8-9, liu2024molecularmechanismsunderlying media 1e06fe05)

The same work connects BIRC6 to LC3 K51 ubiquitylation and shows that LC3 K51R produces system-level consequences (increased autophagy; decreased apoptosis), turning a single ubiquitination site into a mechanistic “toggle” for cell fate under stress. (liu2024molecularmechanismsunderlying pages 7-7, liu2024molecularmechanismsunderlying pages 7-8)

### 5.2 2024 ACS Omega: BIRC6–Axin ubiquitination couples IAP biology to Wnt signaling
Zhong et al. (Feb 2024) provide a cancer-relevant substrate/axis (Axin→β‑catenin) for BIRC6 and show that blocking Wnt/β‑catenin signaling (XAV‑939 or β‑catenin knockdown) suppresses BIRC6-driven oncogenic phenotypes and reduces xenograft tumorigenesis (with experimental details including XAV‑939 dosing **2.5 mg/kg IP every other day**). (zhong2024birc6modulatesthe pages 5-8)

## 6) Current applications and real-world implementations

### 6.1 Gene-silencing therapeutic concepts (antisense oligonucleotides)
Patents disclose **dual-targeting antisense oligonucleotides (dASOs)** designed to reduce BIRC6 (Apollon/BRUCE) mRNA (often paired with cIAP1 or survivin targeting), including explicit sequence examples and multiple chemical modification strategies (e.g., phosphorothioate linkages, 2′MOE gapmers) and delivery options (e.g., IV administration; lipid particle mixing). (CA2897389A1 pages 1-4, WO2018129622A1 pages 1-4)

### 6.2 Preclinical in vivo efficacy statistics for BIRC6-directed antisense
In xenograft and PDX settings, dASOs targeting BIRC6 reduced intratumoral BIRC6 protein (reported p-values **p=0.026** and **p=0.006**) and, in an enzalutamide-resistant prostate cancer PDX model, achieved **37% smaller median tumor volume** versus control and increased apoptotic cells (**16% vs 7.5%**, ~2‑fold). (CA2897389A1 pages 19-21)

### 6.3 RNAi/shRNA approaches
Preclinical gene-silencing modalities include reported use of an oncolytic adenovirus delivering shRNA against Apollon/BIRC6 to inhibit tumor growth and enhance 5‑fluorouracil effect (described in translational patent text). (US20170015997A1 pages 38-39)

## 7) Expert opinions / authoritative analysis (within available sources)
A consistent interpretation across the recent mechanistic studies is that BIRC6 acts as a **cell-fate rheostat**: by (i) restraining initiator caspase‑9 and (ii) suppressing autophagy via LC3 ubiquitylation, it can stabilize survival programs under stress, but under conditions that shift LC3 modification state (e.g., K51R or autophagy induction) BIRC6 itself becomes susceptible to autophagic degradation, allowing pro-death programs to proceed. This “mutual regulation” framing is explicitly advanced in the 2024 mechanistic study. (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 7-7)

In cancer models, BIRC6’s E3 activity can be repurposed toward signaling scaffolds such as Axin, linking classical IAP biology to Wnt-driven stemness and therapy resistance—a mechanistic rationale for therapeutic targeting of BIRC6 in RCC and potentially other tumors. (zhong2024birc6modulatesthe pages 3-5, zhong2024birc6modulatesthe pages 5-8)

## 8) Clinical trials and implementation status (disambiguation of ‘APOLLON’)
A ClinicalTrials.gov search for “APOLLON” retrieves trials that are **not** related to BIRC6/Apollon (protein), e.g., a pediatric congenital heart disease trial named “APOLLON” involving autologous cardiac stem/progenitor cell infusion (NCT02781922). This is a **name collision**, not a BIRC6-targeting study. (NCT02781922 chunk 1)

Within the retrieved trial set, no interventional clinical trial directly targeting BIRC6 (as a drug target) was identified. (NCT02781922 chunk 1)

## 9) Summary of BIRC6 functional annotation (concise)
BIRC6 (Q9NR09) is a giant dual-function E2/E3 ubiquitin enzyme with a BIR domain that binds caspase regulators and a UBC domain enabling ubiquitin transfer. Recent cryo‑EM and mechanistic work position BIRC6 as a central coordinator of apoptosis–autophagy crosstalk through (i) preferential inhibition/engagement of caspase‑9 and (ii) UBA6‑coupled mono‑ubiquitylation of LC3 at K51, which suppresses autophagy and promotes apoptotic susceptibility; conversely, autophagy induction can drive BIRC6 turnover and reduce caspase‑9 abundance. In RCC, BIRC6 expands its substrate repertoire to Axin, activating Wnt/β‑catenin signaling and promoting tumor growth/stemness/drug resistance. Translationally, BIRC6 is being explored mainly through gene-silencing modalities (antisense, shRNA), with preclinical xenograft/PDX efficacy but no clear direct BIRC6-targeting clinical trials in the retrieved evidence. (liu2024molecularmechanismsunderlying pages 1-2, liu2024molecularmechanismsunderlying pages 7-7, zhong2024birc6modulatesthe pages 3-5, zhong2024birc6modulatesthe pages 5-8, CA2897389A1 pages 19-21)

---

## Key functional evidence table

| Function / Process | Molecular Mechanism | Key Evidence / Findings | Subcellular Localization / Complex | Primary Source |
| :--- | :--- | :--- | :--- | :--- |
| **Apoptosis Inhibition** | Dual E2/E3 ubiquitin ligase; forms anti-parallel U-shaped dimer via UBC, BIR, and other domains. Binds **Smac/DIABLO** in central cavity. Ubiquitylates **Caspase-9** (active and pro-forms) for degradation. | **Smac** outcompetes Caspase-3/HtrA2 but *not* Procaspase-9 for BIRC6 binding. Rapamycin (autophagy inducer) shortens Procaspase-9 half-life from ~12h to <8h (reversed by Baf A1). | Cytoplasmic dimer; Complexes with Smac, Caspase-9, and UBA6 (E1). | [Liu et al., *Nat Commun*, 2024](https://doi.org/10.1038/s41467-024-45222-1) (Jan 2024) |
| **Autophagy Regulation** | Cooperates with **UBA6** (E1) to monoubiquitylate **LC3** at residue **K51**. Dimerization may occlude the LIR motif, regulating LC3 access. | **LC3 K51R** mutation (non-ubiquitylatable) increases LC3-II/I ratio and autophagic flux. LIR1 peptide (NPQTSSFLQVLV) competes for LC3 binding (100 µM enhances, ~400 µM inhibits). | Co-localizes with LC3. BIRC6 itself degraded by autophagy upon induction. | [Liu et al., *Nat Commun*, 2024](https://doi.org/10.1038/s41467-024-45222-1) (Jan 2024) |
| **LC3B Turnover** | E3 ligase activity targets **LC3B** for proteasomal degradation (antagonized by UBE2M-mediated neddylation at K42). | Knockdown of BIRC6 reduces ubiquitination of **LC3B K42R** mutant. MG132 treatment rescues LC3B levels. Confirms K51 as primary ubiquitination site. | Cytoplasmic complex with LC3B. | [Xu et al., *PNAS*, 2025](https://doi.org/10.1073/pnas.2411429122) (Apr 2025) |
| **Wnt Signaling / Cancer Progression** | E3 ligase for **Axin**. Promotes Axin ubiquitination and degradation, stabilizing **β-catenin**. Associates with SIAH1. | Overexpression decreases Axin protein half-life (CHX chase). **XAV-939** (10 µM) or β-catenin KD reverses BIRC6-driven renal cancer cell growth/invasion (P < 0.001). | Cytoplasmic colocalization with Axin. | [Zhong et al., *ACS Omega*, 2024](https://doi.org/10.1021/acsomega.3c07265) (Feb 2024) |
| **Caspase Binding** | BIR domain binds active caspases. | Identified binding to active **Caspases-3, -6, -7, and -9**. Protein mass ~528 kDa. | Cytoplasmic / Apoptosome-related. | [Patent US20170015997A1](https://patents.google.com/patent/US20170015997A1) (2017) |


*Table: Table summarizing the primary molecular functions, mechanisms, quantitative experimental evidence, and subcellular localization of BIRC6 based on 2024-2025 literature.*

---

## Key references (URLs + publication dates)
- **Liu et al.** “Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy.” *Nature Communications*. **Jan 2024**. https://doi.org/10.1038/s41467-024-45222-1 (liu2024molecularmechanismsunderlying pages 1-2)
- **Zhong et al.** “BIRC6 Modulates the Protein Stability of Axin…” *ACS Omega*. **Feb 2024**. https://doi.org/10.1021/acsomega.3c07265 (zhong2024birc6modulatesthe pages 1-2)
- **Xu et al.** “Neddylation modification stabilizes LC3B…” *PNAS*. **Apr 2025**. https://doi.org/10.1073/pnas.2411429122 (xu2025neddylationmodificationstabilizes pages 6-7)
- **Patent** (Y. Wang) “Dual targeting antisense oligonucleotides as apoptotic inhibitor therapeutic …” **2017**. https://patents.google.com/patent/US20170015997A1 (US20170015997A1 pages 19-29)
- **Clinical trial name collision example**: “APOLLON Trial” (cardiac cell therapy; not BIRC6 protein). NCT02781922. First posted **May 25, 2016**; last update posted **Sep 30, 2025**. (NCT02781922 chunk 1)


References

1. (liu2024molecularmechanismsunderlying pages 1-2): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

2. (US20170015997A1 pages 19-29): Yuzhuo Wang. Dual targeting antisense oligonucleotides as apoptotic inhibtor therapeutic …. Patent (US), 2017.

3. (liu2024molecularmechanismsunderlying pages 7-7): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

4. (liu2024molecularmechanismsunderlying pages 8-9): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

5. (liu2024molecularmechanismsunderlying pages 7-8): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

6. (xu2025neddylationmodificationstabilizes pages 6-7): Linlin Xu, Xinxing Lyu, Yibo Wang, Li Ni, Pin Li, Piao Zeng, Qixia Wang, Yunhao Chang, Chenglong Pan, Qingxia Hu, Shuhong Huang, and Ningning Dang. Neddylation modification stabilizes lc3b by antagonizing its ubiquitin-mediated degradation and promoting autophagy in skin. Proceedings of the National Academy of Sciences of the United States of America, Apr 2025. URL: https://doi.org/10.1073/pnas.2411429122, doi:10.1073/pnas.2411429122. This article has 2 citations and is from a highest quality peer-reviewed journal.

7. (liu2024molecularmechanismsunderlying pages 4-5): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

8. (zhong2024birc6modulatesthe pages 3-5): Kaihua Zhong, Xiaohong Wang, Heyuan Zhang, Nanhui Chen, Yang Mai, Sipin Dai, Lawei Yang, Dong Chen, and Weifeng Zhong. Birc6 modulates the protein stability of axin to regulate the growth, stemness, and resistance of renal cancer cells via the β-catenin pathway. ACS Omega, 9:7782-7792, Feb 2024. URL: https://doi.org/10.1021/acsomega.3c07265, doi:10.1021/acsomega.3c07265. This article has 6 citations and is from a peer-reviewed journal.

9. (zhong2024birc6modulatesthe pages 1-2): Kaihua Zhong, Xiaohong Wang, Heyuan Zhang, Nanhui Chen, Yang Mai, Sipin Dai, Lawei Yang, Dong Chen, and Weifeng Zhong. Birc6 modulates the protein stability of axin to regulate the growth, stemness, and resistance of renal cancer cells via the β-catenin pathway. ACS Omega, 9:7782-7792, Feb 2024. URL: https://doi.org/10.1021/acsomega.3c07265, doi:10.1021/acsomega.3c07265. This article has 6 citations and is from a peer-reviewed journal.

10. (zhong2024birc6modulatesthe pages 5-8): Kaihua Zhong, Xiaohong Wang, Heyuan Zhang, Nanhui Chen, Yang Mai, Sipin Dai, Lawei Yang, Dong Chen, and Weifeng Zhong. Birc6 modulates the protein stability of axin to regulate the growth, stemness, and resistance of renal cancer cells via the β-catenin pathway. ACS Omega, 9:7782-7792, Feb 2024. URL: https://doi.org/10.1021/acsomega.3c07265, doi:10.1021/acsomega.3c07265. This article has 6 citations and is from a peer-reviewed journal.

11. (liu2024molecularmechanismsunderlying media efc726e5): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

12. (liu2024molecularmechanismsunderlying media 1e06fe05): Shuo-Shuo Liu, Tian-Xia Jiang, Fan Bu, Ji-Lan Zhao, Guang-Fei Wang, Guo-Heng Yang, Jie-Yan Kong, Yun-Fan Qie, Pei Wen, Li-Bin Fan, Ning-Ning Li, Ning Gao, and Xiao-Bo Qiu. Molecular mechanisms underlying the birc6-mediated regulation of apoptosis and autophagy. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-024-45222-1, doi:10.1038/s41467-024-45222-1. This article has 26 citations and is from a highest quality peer-reviewed journal.

13. (CA2897389A1 pages 1-4): Yuzhuo WANG. Dual targeting antisense oligonucleotides as apoptotic inhibtor therapeutic …. Patent (CA), 2017.

14. (WO2018129622A1 pages 1-4): Yuzhuo WANG. Dual targeting antisense oligonucleotides for use as apoptotic inhibitors for …. Patent (WO), 2018.

15. (CA2897389A1 pages 19-21): Yuzhuo WANG. Dual targeting antisense oligonucleotides as apoptotic inhibtor therapeutic …. Patent (CA), 2017.

16. (US20170015997A1 pages 38-39): Yuzhuo Wang. Dual targeting antisense oligonucleotides as apoptotic inhibtor therapeutic …. Patent (US), 2017.

17. (NCT02781922 chunk 1):  Cardiac Stem/Progenitor Cell Infusion in Univentricular Physiology (APOLLON Trial). Metcela Inc.. 2016. ClinicalTrials.gov Identifier: NCT02781922

## Citations

1. liu2024molecularmechanismsunderlying pages 7-7
2. xu2025neddylationmodificationstabilizes pages 6-7
3. liu2024molecularmechanismsunderlying pages 4-5
4. liu2024molecularmechanismsunderlying pages 1-2
5. liu2024molecularmechanismsunderlying pages 8-9
6. liu2024molecularmechanismsunderlying pages 7-8
7. Liu et al., *Nat Commun*, 2024
8. Xu et al., *PNAS*, 2025
9. Zhong et al., *ACS Omega*, 2024
10. Patent US20170015997A1
11. https://doi.org/10.1038/s41467-024-45222-1
12. https://doi.org/10.1073/pnas.2411429122
13. https://doi.org/10.1021/acsomega.3c07265
14. https://patents.google.com/patent/US20170015997A1
15. https://doi.org/10.1038/s41467-024-45222-1,
16. https://doi.org/10.1073/pnas.2411429122,
17. https://doi.org/10.1021/acsomega.3c07265,