# Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe **Authors:** Fanghui Ge, Jingxuan Shu, Ziqian Liu, Hong Zhang, Jiandong Wang PMC · DOI: 10.3390/biology15040302 · Biology · 2026-02-09 ## TL;DR NIX/BNIP3L can both kill and protect cancer cells, and understanding its dual roles may improve cancer treatments. ## Contribution This paper systematically reviews NIX/BNIP3L's structure, function, and dual roles in various cancers to guide personalized cancer therapy. ## Key findings - NIX/BNIP3L mediates apoptosis to inhibit tumor growth. - NIX/BNIP3L promotes tumor cell survival by eliminating ROS through mitophagy. - Its roles in multiple cancers suggest potential for targeted therapies. ## Abstract As a mitochondrial outer membrane protein, NIX/BNIP3L not only mediates apoptosis to inhibit tumor growth, but also promotes tumor cell survival by eliminating intracellular ROS via mitophagy. Through a systematic summary of the gene structure of NIX, the pathways of biogenesis and degradation, the mechanisms by which it orchestrates apoptosis and mitophagy, and the roles in glioblastoma, lung cancer, hepatocellular carcinoma, breast cancer, pancreatic cancer, colorectal cancer, and hematological malignancies, we anticipate providing a novel theoretical foundation for the personalized treatment and prognosis of cancer patients. Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L generation and degradation, the role of NIX/BNIP3L in mediating apoptosis and mitophagy and to advance the understanding of the roles of NIX/BNIP3L in glioblastoma, lung cancer, hepatocellular carcinoma, breast cancer, pancreatic cancer, colorectal cancer and hematologic neoplasms, aiming to enhance treatment precision and improve patient outcomes. ## Linked entities - **Genes:** BNIP3L (BCL2 interacting protein 3 like) [NCBI Gene 665], BNIP3L (BCL2 interacting protein 3 like) [NCBI Gene 665] - **Diseases:** glioblastoma (MONDO:0018177), lung cancer (MONDO:0005138), hepatocellular carcinoma (MONDO:0007256), breast cancer (MONDO:0004989), pancreatic cancer (MONDO:0005192), colorectal cancer (MONDO:0005575) ## Full-text entities - **Genes:** Bnip3l (BCL2/adenovirus E1B interacting protein 3-like) [NCBI Gene 12177] {aka D14Ertd719e, Nip3L, Nix}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CASP9 (caspase 9) [NCBI Gene 842] {aka APAF-3, APAF3, ICE-LAP6, MCH6, PPP1R56}, BNIP3 (BCL2 interacting protein 3) [NCBI Gene 664] {aka HABON, NIP3}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, TNFRSF10B (TNF receptor superfamily member 10b) [NCBI Gene 8795] {aka CD262, DR5, KILLER, KILLER/DR5, TRAIL-R2, TRAILR2}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb}, CCNA2 (cyclin A2) [NCBI Gene 890] {aka CCN1, CCNA}, CYCS (cytochrome c, somatic) [NCBI Gene 54205] {aka CYC, HCS, THC4}, Ptk2 (PTK2 protein tyrosine kinase 2) [NCBI Gene 14083] {aka FADK 1, FAK, FRNK, Fadk, p125FAK}, MUL1 (mitochondrial E3 ubiquitin protein ligase 1) [NCBI Gene 79594] {aka C1orf166, GIDE, MAPL, MULAN, RNF218}, PLAU (plasminogen activator, urokinase) [NCBI Gene 5328] {aka ATF, BDPLT5, QPD, UPA, URK, u-PA}, NADK2 (NAD kinase 2, mitochondrial) [NCBI Gene 133686] {aka C5orf33, DECRD, MNADK, NADKD1}, REXO2 (RNA exonuclease 2) [NCBI Gene 25996] {aka CGI-114, REX2, RFN, SFN}, Src (src proto-oncogene, non-receptor tyrosine kinase) [NCBI Gene 20779] {aka pp60c-src}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, FUNDC1 (FUN14 domain containing 1) [NCBI Gene 139341], Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], ROR1 (ROR family WNT receptor 1) [NCBI Gene 4919] {aka NTRKR1, dJ537F10.1}, MAP1LC3A (microtubule associated protein 1 light chain 3 alpha) [NCBI Gene 84557] {aka ATG8E, LC3, LC3A, MAP1ALC3, MAP1BLC3}, KDM3A (lysine demethylase 3A) [NCBI Gene 55818] {aka JHDM2A, JHMD2A, JMJD1, JMJD1A, TSGA}, Atg5 (autophagy related 5) [NCBI Gene 11793] {aka 2010107M05Rik, 3110067M24Rik, Apg5l, Atg5l, Paddy}, JUN (Jun proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 3725] {aka AP-1, AP1, c-Jun, cJUN, p39}, ITGB4 (integrin subunit beta 4) [NCBI Gene 3691] {aka CD104, GP150, JEB5A, JEB5B}, HBx [NCBI Gene 944566], TNFSF10 (TNF superfamily member 10) [NCBI Gene 8743] {aka APO2L, Apo-2L, CD253, TANCR, TL2, TNLG6A}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, BAX (BCL2 associated X, apoptosis regulator) [NCBI Gene 581] {aka BCL2L4}, SPATA2 (spermatogenesis associated 2) [NCBI Gene 9825] {aka PD1, PPP1R145, tamo}, APAF1 (apoptotic peptidase activating factor 1) [NCBI Gene 317] {aka APAF-1, CED4}, GPR176 (G protein-coupled receptor 176) [NCBI Gene 11245] {aka HB-954}, FBP1 (fructose-bisphosphatase 1) [NCBI Gene 2203] {aka FBP}, PRKN (parkin RBR E3 ubiquitin protein ligase) [NCBI Gene 5071] {aka AR-JP, LPRS2, PARK2, PDJ}, Bax (BCL2-associated X protein) [NCBI Gene 12028], BNIP3L (BCL2 interacting protein 3 like) [NCBI Gene 665] {aka BNIP3a, NIP3L, NIX}, GNAS (GNAS complex locus) [NCBI Gene 2778] {aka AHO, AIMAH1, C20orf45, GNAS1, GPSA, GSA}, Ulk1 (unc-51 like kinase 1) [NCBI Gene 22241] {aka Unc51.1, mKIAA0722}, GABARAPL1 (GABA type A receptor associated protein like 1) [NCBI Gene 23710] {aka APG8-LIKE, APG8L, ATG8, ATG8B, ATG8L, GEC1}, RHEB (Ras homolog, mTORC1 binding) [NCBI Gene 6009] {aka RHEB2}, CAV1 (caveolin 1) [NCBI Gene 857] {aka BSCL3, CGL3, LCCNS, MSTP085, PPH3, VIP21}, WIPI2 (WD repeat domain, phosphoinositide interacting 2) [NCBI Gene 26100] {aka ATG18B, Atg21, CGI-50, IDDSSA, WIPI-2}, ULK1 (unc-51 like autophagy activating kinase 1) [NCBI Gene 8408] {aka ATG1, ATG1A, UNC51, Unc51.1, hATG1}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, FOXO3 (forkhead box O3) [NCBI Gene 2309] {aka AF6q21, FKHRL1, FKHRL1P2, FOXO2, FOXO3A}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, BECN1 (beclin 1) [NCBI Gene 8678] {aka ATG6, VPS30, beclin1}, RORA (RAR related orphan receptor A) [NCBI Gene 6095] {aka IDDECA, NR1F1, ROR1, ROR2, ROR3, RORa1}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, HLA-G (major histocompatibility complex, class I, G) [NCBI Gene 3135] {aka MHC-G}, SQSTM1 (sequestosome 1) [NCBI Gene 8878] {aka A170, DMRV, EBIAP, FTDALS3, NADGP, OSIL}, CAMP (cathelicidin antimicrobial peptide) [NCBI Gene 820] {aka CAP-18, CAP18, CRAMP, FALL-39, FALL39, HSD26}, NGFR (nerve growth factor receptor) [NCBI Gene 4804] {aka CD271, Gp80-LNGFR, TNFRSF16, p75(NTR), p75NTR}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, Mdk (midkine) [NCBI Gene 17242] {aka MK, Mek}, PTK2B (protein tyrosine kinase 2 beta) [NCBI Gene 2185] {aka CADTK, CAKB, FADK2, FAK2, PKB, PTK}, Bcl2l1 (BCL2-like 1) [NCBI Gene 12048] {aka Bcl(X)L, Bcl-XL, Bcl2l, BclX, bcl-x, bcl2-L-1}, MAPK14 (mitogen-activated protein kinase 14) [NCBI Gene 1432] {aka CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2}, H3P16 (H3 histone pseudogene 16) [NCBI Gene 644914] {aka H3.6, H3F3AP6, p21} - **Diseases:** alopecia (MESH:D000505), hypoxic (MESH:D002534), LUAD (MESH:D000077192), erythroleukemia (MESH:D004915), tumorigenesis (MESH:D063646), AML (MESH:D015470), MDS (MESH:D009190), Hematologic Neoplasms (MESH:D019337), triple (MESH:C536008), lung squamous cell carcinomas (MESH:D002294), NSCLC (MESH:D002289), hypoxia (MESH:D000860), PDAC (MESH:D021441), injury to (MESH:D014947), osteosarcoma (MESH:D012516), inflammatory (MESH:D007249), glioma (MESH:D005910), pain (MESH:D010146), Pancreatic Cancer (MESH:D010190), mitochondrial damage (MESH:D028361), multiple myeloma (MESH:D009101), Lung Cancer (MESH:D008175), adenocarcinoma (MESH:D000230), Cancer (MESH:D009369), chronic myeloid leukemia (MESH:D015464), clonal hematopoietic stem cell disorders (MESH:D000090267), heme (MESH:D046351), Breast Cancer (MESH:D001943), TNBC (MESH:D064726), HCC (MESH:D006528), intestinal diseases (MESH:D007410), GBM (MESH:D005909), astrocytoma (MESH:D001254), brain malignancy (MESH:D001932), hormone receptor-positive (MESH:D046150), epithelial carcinoma metastasis (MESH:D009375), metastasis (MESH:D009362), reperfusion injury (MESH:D015427), KPC (MESH:C565455), death (MESH:D003643), NIX deficiency (MESH:D007153), Leukemia (MESH:D007938), ICH (MESH:D002543), CRC (MESH:D015179), myocardial ischemia (MESH:D017202), cytotoxic (MESH:D064420) - **Chemicals:** 5-FU (MESH:D005472), imatinib (MESH:D000068877), iron (MESH:D007501), PD2 (MESH:C548432), sorafenib (MESH:D000077157), enediyne (MESH:D053281), DAC (MESH:D000077209), Upamostat (MESH:C580590), diltiazem hydrochloride (MESH:D004110), oxygen (MESH:D010100), L-lactate (MESH:D019344), CCCP (MESH:D002258), pentose phosphate (MESH:D010428), ATP (MESH:D000255), triptolide (MESH:C001899), gallium (MESH:D005708), gemcitabine (MESH:D000093542), glucose (MESH:D005947), creatinine (MESH:D003404), 5-AZA (MESH:D001374), chloroquine (MESH:D002738), ROS (MESH:D017382), Deapioplatycodin D (-), Cisplatin (MESH:D002945), OG (MESH:C016627), ADR (MESH:D004317), Pitavastatin (MESH:C108475), AT-101 (MESH:C028178), NADP+ (MESH:D009249), temozolomide (MESH:D000077204), heme (MESH:D006418), LDM (MESH:C058024), fatty acid (MESH:D005227) - **Species:** Hepatitis B virus (no rank) [taxon 10407], Mus musculus (house mouse, species) [taxon 10090], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Streptomyces (genus) [taxon 1883], Homo sapiens (human, species) [taxon 9606] - **Cell lines:** MDA-MB-453 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0418) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12937734/full.md ## Figures 1 figure with captions in the complete paper: https://tomesphere.com/paper/PMC12937734/full.md ## References 118 references — full list in the complete paper: https://tomesphere.com/paper/PMC12937734/full.md --- Source: https://tomesphere.com/paper/PMC12937734