DECR1

DECR1 encodes mitochondrial 2,4-dienoyl-CoA reductase, an auxiliary enzyme of β-oxidation that reduces unsaturated enoyl-CoA esters with double bonds at even- and odd-numbered positions (PMID:9403065), and functions as the rate-limiting enzyme for β-oxidation of polyunsaturated fatty acids (PUFAs) (PMID:32686647). Its catalytic activity on PUFA substrates is conserved enough to complement a prokaryotic 2,4-dienoyl-CoA reductase mutant, restoring growth on linoleic acid [PMID:bio_10.1101_2025.01.23.634462], and is required for its biological effects, since catalytically impaired mutants fail to suppress de novo fatty acid synthesis and tumorigenesis (PMID:17636013). Across prostate, breast, cardiac, vascular, and placental cell types, loss of DECR1 blocks PUFA catabolism, leading to accumulation of PUFA-containing phospholipids, lipid peroxidation, and ferroptosis, the latter coupled to the SLC7A11/GPX4 axis (PMID:32686647, PMID:39427521, PMID:40467779, PMID:41862008). Genetic ablation in mice confirms a selective defect in unsaturated—but not saturated—fatty acid breakdown, impairing brown adipose tissue thermogenesis (PMID:31427678). DECR1 expression is constrained by androgen receptor signaling as a negatively regulated AR target (PMID:32686647) and induced by BMP9 to support cardiac mitochondrial bioenergetics during myocardial infarction (PMID:39315433). Beyond its enzymatic role, DECR1 engages protein partners that shape lipid metabolism: it directly binds hormone-sensitive lipase to promote its phosphorylation, lipid-droplet translocation, and lipolysis (PMID:34896618), binds PDK4 to drive an HDAC3–HADHA deacetylation cascade amplifying mitochondrial FAO in cardiac injury (PMID:40052435), and its delivery into mitochondria depends on high-affinity binding by the GIPC1 PDZ domain (KD = 16.3 nM) for actin-dependent transport, loss of which depletes mitochondrial DECR1 and promotes ferroptosis (PMID:41787053). Mouse Decr1 also forms a high-affinity complex with 2'-5' oligoadenylates resolved at 1.4 Å, a species-specific interaction without an identified antiviral or regulatory function (PMID:37676257).

1. 1997 High

   Established the molecular identity of human DECR1 as a mitochondrial β-oxidation auxiliary enzyme, providing the gene, locus, and enzymatic assignment needed for all subsequent functional work.

   Evidence Molecular cloning, primer extension, 5' RACE, and FISH chromosomal mapping

   PMID:9403065

   Open questions at the time

   • No structural model of the human enzyme
   • Substrate range characterized only enzymatically, not in cellular flux
2. 2007 High

   Showed that DECR1's catalytic activity, not merely its presence, drives suppression of de novo lipogenesis and tumorigenesis, tying the enzyme to a metabolic-tumor-suppressor role.

   Evidence Active-site mutant expression with in vivo xenograft tumorigenicity and de novo fatty acid synthesis assays in ErbB2/Neu breast cancer cells

   PMID:17636013

   Open questions at the time

   • Mechanism linking PUFA reduction to ErbB2/Neu suppression not defined
   • Context appears opposite to later pro-tumor roles, unresolved
3. 2019 High

   Genetic knockout established in vivo that DECR1 is specifically required for unsaturated, not saturated, fatty acid β-oxidation, with physiological consequences for thermogenesis.

   Evidence Decr-/- mouse with calorimetry, thermography, lipidomics, and lipolysis assays

   PMID:31427678

   Open questions at the time

   • Identity of the suppressive unsaturated metabolites incompletely defined
   • Link to NE signaling mechanistically indirect
4. 2020 High

   Defined DECR1 as the rate-limiting PUFA β-oxidation enzyme whose loss triggers lipid peroxidation and ferroptosis, and placed it under negative AR transcriptional control, framing it as a cancer vulnerability.

   Evidence siRNA knockdown, β-oxidation flux, lipid peroxidation/ROS, xenografts, ex vivo tumors, and AR ChIP in prostate cancer

   PMID:32686647

   Open questions at the time

   • Does not resolve why DECR1 is tumor-suppressive in some contexts and pro-tumor in others
   • AR-binding site fine mapping not detailed
5. 2021 Medium

   Revealed a non-enzymatic protein-partner role: DECR1 binds and activates HSL to promote lipolysis, expanding its function beyond catalysis.

   Evidence Co-IP, overexpression/silencing, HSL phosphorylation/activity and lipid-droplet translocation imaging in cervical cancer cells

   PMID:34896618

   Open questions at the time

   • Single Co-IP without reciprocal or structural validation
   • Direct binding interface not mapped
6. 2023 High

   Determined that mouse Decr1 binds 2'-5' oligoadenylates at atomic resolution, defining species-specific recognition but explicitly finding no antiviral or regulatory function.

   Evidence MS pull-down, biochemical binding, and 1.4 Å co-crystal structure

   PMID:37676257

   Open questions at the time

   • Functional significance of the OA complex undefined
   • Interaction absent in human DECR1
7. 2024 Medium

   Connected DECR1 to upstream BMP9 signaling and a downstream PDK4–HDAC3–HADHA deacetylation cascade, linking it to cardiac mitochondrial bioenergetics and FAO amplification.

   Evidence AAV expression/knockdown, KO mice, recombinant BMP9, Co-IP (DECR1-PDK4), and epistasis rescue in MI and diabetic cardiomyopathy models

   PMID:39315433 PMID:40052435

   Open questions at the time

   • Biochemical mechanism of BMP9→DECR1 regulation undefined
   • DECR1-PDK4 interaction from single-lab Co-IP without structure
8. 2024 Medium

   Placed DECR1 in a ferroptosis-regulatory axis with SLC7A11 and identified it as a degradation target of bufalin, linking its protein stability to ferroptosis outcomes.

   Evidence High-content screening, Co-IP (DECR1-SLC7A11), autophagy/ubiquitination inhibitor assays, and overexpression rescue in breast cancer

   PMID:39427521

   Open questions at the time

   • Direct vs. indirect nature of DECR1-SLC7A11 interaction unresolved
   • Single-lab Co-IP without reciprocal validation
9. 2025 Medium

   Detailed the lipid-metabolic basis of DECR1-loss ferroptosis as a PC/AA axis with ACSL4/PLA2G12A upregulation and GPX4/SLC7A11 loss, and confirmed enzymatic conservation by bacterial complementation.

   Evidence Multi-omics with metabolite validation in breast cancer; E. coli fadH complementation on linoleic acid (preprint)

   PMID:40467779 PMID:bio_10.1101_2025.01.23.634462

   Open questions at the time

   • Complementation is preprint without mutagenesis
   • Causal ordering within the PC/AA axis not fully dissected
10. 2026 High

    Identified the mechanism of DECR1 mitochondrial delivery through high-affinity GIPC1 PDZ binding and actin transport, explaining how localization controls PUFA-phospholipid clearance and ferroptosis susceptibility.

    Evidence Co-IP/MS, SPR (KD = 16.3 nM), IF colocalization, GIPC1 cardiac KO mouse, and DECR1 rescue

    PMID:41787053

    Open questions at the time

    • Whether GIPC1 transport applies across all tissues unknown
    • Import machinery downstream of actin delivery not defined
11. 2026 Medium

    Extended the DECR1 ferroptosis/mitochondrial-quality role to additional tissues, implicating it in preeclampsia trophoblast pathology and vascular calcification via NF-κB/NLRP3.

    Evidence Genetic/pharmacological DECR1 modulation in trophoblast PE and VSMC calcification models with in vivo readouts and molecular docking of small-molecule binders

    PMID:41862008 PMID:42034130

    Open questions at the time

    • Direct DECR1 binding of ursolic acid not reconstituted in vitro
    • Link between metabolic activity and NF-κB/NLRP3 indirect
12. 2025 Low

    Proposed an epitranscriptomic regulatory layer in which FTO-MZF1 controls DECR1 expression during cardiac ischemia/reperfusion injury.

    Evidence m6A analysis, FTO gain/loss, MZF1 reporter assays, and cardiomyocyte injury readouts

    PMID:41003915

    Open questions at the time

    • No direct DECR1 enzymatic or protein-level validation in this axis
    • MZF1 binding to DECR1 promoter inferred from reporters only

• It remains unresolved why DECR1 acts as a metabolic tumor suppressor in some contexts yet as a pro-survival, pro-disease factor in others, and how its catalytic versus protein-scaffold functions are partitioned.
• No unified model reconciling tumor-suppressive and pro-tumor/pro-injury roles
• Relative contribution of enzymatic vs. binding (HSL, PDK4, SLC7A11) functions undefined
• Human structural model and import pathway incomplete