AKR1C4
aldo-keto reductase family 1 member C4
Theoretical — per Powers
Gene summary
A protein-coding gene on chromosome 10 (steroid hormone synthesis, steroid conjugation and clearance). Encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors.
Source: NCBI Gene, accessed 2026-10-07.
Protein reference (UniProt)
- Protein
Aldo-keto reductase family 1 member C4
- Function (excerpt)
Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 3alpha/beta-, 17beta- and 20alpha-hydroxysteroids. Required for male sex determination as a component of the 'backdoor' androgen biosynthesis pathway that generates 5alpha-dihydrotestosterone (5alpha-DHT) via pregnanes. Acts together with AKR1C2 to convert 5alpha-dihydroprogesterone (5alpha-DHP) to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP/allopregnanolone), leading to 5alpha-DHT secretion necessary for embryonic gonad differentiation into testis. May regulate the concentrations of circulating neurosteroids.
- Pathway
Steroid metabolism.
- Subcellular location
Cytoplasm, cytosol.
- Tissue specificity
Expressed in liver. Expressed in fetal and adult testes and adrenal glands.
- Associated conditions
46,XY sex reversal 8 (SRXY8).
Source: UniProtKB/Swiss-Prot P17516, release 2026_03, licensed CC BY 4.0. This is the protein’s normal biology, not evidence about post-drug syndromes; associated conditions are inherited disorders of the gene, not PFS, PSSD or PRSD.
Why its pathway is in the library
Steroid-synthesis enzymes sit directly on the pathways perturbed by 5-alpha-reductase inhibitors and SSRIs; inherited variation here is a candidate susceptibility factor for persistent post-drug phenotypes. Steroid clearance is the exit route for androgens and their metabolites — the pathway at the center of Powers' PFS model (defective glucuronidation/sulfation trapping androgens intracellularly). Gut bacterial enzymes can undo this clearance, linking it to the microbiome thread.
Written for the whole steroid synthesis / conjugation & clearance family, not for AKR1C4 specifically.
Powers’ note (his unpublished theorizing)
Named by Powers (DWP-002 2026 model; DWP-003, unpublished): upregulated 3α-HSD (AKR1C2/AKR1C4) is his proposed enzymatic bridge overproducing downstream metabolites and cerebral THDOC in the 2026 neurosteroid-excess model.
Narrative library record
Function
3-alpha-hydroxysteroid dehydrogenase type 1; liver-restricted isoform that reduces 3-keto-5-dihydrosteroids to tetrahydro products and participates in neurosteroid synthesis. Loss of AKR1C4 alone does not cause developmental phenotypes but can worsen the effects of AKR1C2 variants.
Corpus relevance
Completes the AKR1C cluster in Powers' DWP-001 susceptibility model; its liver-restricted expression is relevant because systemic steroid clearance runs through the liver. Attribution: theoretical-per-Powers.
Powers’ claims naming AKR1C4
- Powers gene claim
AKR1C1; AKR1C2; AKR1C3; AKR1C4 — defects (unspecified)
Confidence: direct
Defects in AKR1C enzymes can contribute, but their products are mostly cleared via glucuronidation — so a bad glucuronidation enzyme (UGT2B1X) is the more fundamental defect. AKR1C enzymes and SRD5A1 are also epigenetically silenceable, and valproic acid may…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1PGL-AKR1C1-AKR1C2-AKR1C3-AKR1C4circa May 2026PFS - Powers gene claim
3α-HSD (3α-hydroxysteroid oxidoreductase/dehydrogenase; encoded by AKR1C2/AKR1C4) — upregulated (acquired)
Confidence: direct
Upregulated 3α-HSD acts as the enzymatic bridge overproducing downstream metabolites (3α-androstanediol, 3α-ADG) and, critically, cerebral THDOC — a GABA-A positive allosteric modulator. Chronic excess remodels downstream neural networks (benzodiazepine…
AKR1C2AKR1C4
Mentioned in 5 corpus records
- Powers · Reddit post
I think I have figured out at least one specific phenotype of PFS, and it is different from the "allopregnanolone" theory
u/drwillpowers · r/DrWillPowers
Powers' key genetics-first post: he proposed a specific PFS phenotype whose "base, core defect" is defective UGT2B17, disabling testosterone's main glucuronidation exit pathway. Carriers show shockingly low 3α-androstanediol glucuronide and near-zero urinary…
AKR1C1AKR1C2AKR1C3AKR1C4HSD17B2+3DWP-0032026PFSCore corpus - Conference abstract
Novel mechanisms of testosterone detoxification in UGT2B17 gene deletion carriers and androgen activation by gut microbiome
Abdul Basit; John Amory; Cindy Li; Vijay Mettu; Scott Heyward; Parth B. Jariwala; Matthew R. Redinbo; Bhagwat Prasad · The FASEB Journal (Experimental Biology meeting abstract)
Proteomic comparison of human livers from UGT2B17 deletion carriers versus high expressors found upregulation of alternative steroid-metabolizing pathways (AKR1D1, AKR1C4, and related dehydrogenases/alcohol dehydrogenases) in deletion carriers, redirecting…
AKR1C4AKR1D1UGT2B17UGT2B7MECH-0142021Systems review · Oct 2026 - Gene recordPowers’ theory
AKR1C1 — aldo-keto reductase family 1 member C1
10p15-p14 (AKR1C gene cluster, chromosome 10)
Cytosolic NAD(P)H-dependent oxidoreductase with mainly 20-alpha-hydroxysteroid dehydrogenase activity; converts progesterone to the inactive 20-alpha-hydroxyprogesterone and also reduces a range of aldehydes, ketones, and xenobiotics. One of four closely…
AKR1C1AKR1C2AKR1C3AKR1C4SRD5A1+1GENE-AKR1C1PFSCore corpus - Gene recordPowers’ theory
AKR1C2 — aldo-keto reductase family 1 member C2
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 3; interconverts DHT and the much weaker 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol), effectively switching DHT's androgenic signal off, and participates in synthesis of neurosteroids such as…
AKR1C1AKR1C2AKR1C3AKR1C4AR+1GENE-AKR1C2PFSCore corpus - Gene recordPowers’ theory
AKR1C3 — aldo-keto reductase family 1 member C3
10p15-p14 (AKR1C gene cluster, chromosome 10)
3-alpha-hydroxysteroid dehydrogenase type 2 (also 17-beta-hydroxysteroid dehydrogenase type 5); metabolizes prostaglandins, estrogens, and progesterone in addition to androgens, and is overexpressed in prostate cancer. Broadest substrate range of the four…
AKR1C1AKR1C2AKR1C3AKR1C4CYP19A1GENE-AKR1C3Core corpus
Also in steroid hormone synthesis
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steroid 5 alpha-reductase 2
chr 2· Steroid synthesis· 19 records - SRD5A1Powers
steroid 5 alpha-reductase 1
chr 5· Steroid synthesis· 17 records - AKR1C2Powers
aldo-keto reductase family 1 member C2
chr 10· Steroid synthesis· 12 records - AKR1C3Powers
aldo-keto reductase family 1 member C3
chr 10· Steroid synthesis· 9 records - CYP17A1
cytochrome P450 family 17 subfamily A member 1
chr 10· Steroid synthesis· 9 records - AKR1C1Powers
aldo-keto reductase family 1 member C1
chr 10· Steroid synthesis· 7 records - HSD3B2
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
chr 1· Steroid synthesis· 7 records - SRD5A3
steroid 5 alpha-reductase 3
chr 4· Steroid synthesis· 6 records
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