Metabolic dysfunction-associated steatohepatitis

Summary

Metabolic dysfunction-associated steatohepatitis (MONDO:0007027) is a disease with 10 cohort genes (13 GWAS associations across 3 studies) and 562 clinical trials. Top therapeutic interventions include pioglitazone, vitamin e, and obeticholic acid.

At a glance

• Cohort genes: 10
• GWAS associations: 13
• Clinical trials: 562

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	metabolic dysfunction-associated steatohepatitis
Mondo ID	MONDO:0007027
EFO	EFO:1001249
DOID	DOID:0080547
ICD-10-CM	K75.81
ICD-11	1884917970
NCIT	C84445
UMLS	C3241937
MedGen	469032
MedDRA	10053219
Is cancer (heuristic)	no

Also known as: MASH · NASH · NASH - nonalcoholic steatohepatitis · non-alcoholic steatohepatitis · nonalcoholic steatohepatitis

Data availability: 13 GWAS associations (3 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hepatobiliary disorder › liver disorder › hepatitis › metabolic dysfunction-associated steatohepatitis

Related subtypes (8): alcoholic hepatitis, drug-induced hepatitis, granulomatous hepatitis, hepatic tuberculosis, viral hepatitis, autoimmune hepatitis, fulminant viral hepatitis, idiopathic peliosis hepatis

Genetics & variants

GWAS landscape

13 GWAS associations across 3 studies. Top hits map to 10 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs738409	3e-44	PNPLA3	?	2.05
rs12077210	4e-09	LEPROT, LEPR	?	1.67
rs2896019	2e-08	PNPLA3	G	3.37
rs80084600	7e-08	LINC01036	?	1.98
rs8107974	1e-07	SUGP1	?	1.61
rs13118664	2e-07	HSD17B13	?	1.4
rs58542926	2e-07	TM6SF2	?	1.61
rs9992651	3e-07	HSD17B13	?	1.39
rs1260326	4e-07	GCKR	?	1.3
rs17007417	5e-07	DYSF - RPS20P10	T	2.74
rs2143571	9e-07	SAMM50	A	2.7
rs6571631	7e-06	NDRG2	?
rs6660749	8e-06	C1orf94 - MIR552	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST010861	Anstee QM	2020	836	17,781	Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort.
GCST005309	Kawaguchi T	2018	58	7,672	Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.
GCST004943	Wattacheril J	2017	46	0	Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	0
Tier 3: regulatory	1
Tier 4: intronic/intergenic	9

MAF distribution

Bucket	Variants
common (>=0.05)	13
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	8
missense_variant	2
stop_gained	1
regulatory_region_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs738409	22	43928847	C>A,G,T	0.05	missense_variant	PNPLA3	3e-44	Tier 1: coding
rs12077210	1	65428477	C>T	0.05	intron_variant	LEPROT, LEPR	4e-09	Tier 4: intronic/intergenic
rs2896019	22	43937814	T>G	0.46	intron_variant	PNPLA3	2e-08	Tier 4: intronic/intergenic
rs80084600	1	187379678	A>C,G	0.05	intron_variant	LINC01036	7e-08	Tier 4: intronic/intergenic
rs8107974	19	19277691	A>C,G,T	0.05	intron_variant	SUGP1	1e-07	Tier 4: intronic/intergenic
rs13118664	4	87318457	A>G,T	0.05	intron_variant	HSD17B13	2e-07	Tier 4: intronic/intergenic
rs58542926	19	19268740	C>A,T	0.05	stop_gained	TM6SF2	2e-07	Tier 1: coding
rs9992651	4	87311358	G>A	0.05	intron_variant	HSD17B13	3e-07	Tier 4: intronic/intergenic
rs1260326	2	27508073	T>A,C,G	0.05	missense_variant	GCKR	4e-07	Tier 1: coding
rs17007417	2	71808541	T>A,C,G	0.17	regulatory_region_variant	DYSF - RPS20P10	5e-07	Tier 3: regulatory
rs2143571	22	43995806	G>A,C	0.43	intron_variant	SAMM50	9e-07	Tier 4: intronic/intergenic
rs6571631	14	21063674	C>A,T	0.05	intron_variant	NDRG2	7e-06	Tier 4: intronic/intergenic
rs6660749	1	34349852	G>A,T	0.05	intergenic_variant	C1orf94 - MIR552	8e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYSF	Orphanet:178400	Distal myopathy with anterior tibial onset
DYSF	Orphanet:199329	Congenital myopathy, Paradas type
DYSF	Orphanet:268	Dysferlin-related limb-girdle muscular dystrophy R2
DYSF	Orphanet:45448	Miyoshi myopathy
LEPR	Orphanet:179494	Obesity due to leptin receptor gene deficiency

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TM6SF2	HGNC:11861	ENSG00000213996	Q9BZW4	Transmembrane 6 superfamily member 2	gwas
PNPLA3	HGNC:18590	ENSG00000100344	Q9NST1	1-acylglycerol-3-phosphate O-acyltransferase PNPLA3	gwas
SUGP1	HGNC:18643	ENSG00000105705	Q8IWZ8	SURP and G-patch domain-containing protein 1	gwas
HSD17B13	HGNC:18685	ENSG00000170509	Q7Z5P4	17-beta-hydroxysteroid dehydrogenase 13	gwas
SAMM50	HGNC:24276	ENSG00000100347	Q9Y512	Sorting and assembly machinery component 50 homolog	gwas
ARHGEF40	HGNC:25516	ENSG00000165801	Q8TER5	Rho guanine nucleotide exchange factor 40	gwas
C1orf94	HGNC:28250	ENSG00000142698	Q6P1W5	Uncharacterized protein C1orf94	gwas
DYSF	HGNC:3097	ENSG00000135636	O75923	Dysferlin	gwas
LEPR	HGNC:6554	ENSG00000116678	P48357	Leptin receptor	gwas
MAP4K5	HGNC:6867	ENSG00000012983	Q9Y4K4	Mitogen-activated protein kinase kinase kinase kinase 5	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TM6SF2	Transmembrane 6 superfamily member 2	Regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.
PNPLA3	1-acylglycerol-3-phosphate O-acyltransferase PNPLA3	Specifically catalyzes coenzyme A (CoA)-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (2-lysophosphatidic acid/LPA) to generate phosphatidic acid (PA), an important metabolic intermediate and precursor for both triglycerides and gl…
SUGP1	SURP and G-patch domain-containing protein 1	Plays a role in pre-mRNA splicing.
HSD17B13	17-beta-hydroxysteroid dehydrogenase 13	Plays a pivotal role in hepatic lipid metabolism.
SAMM50	Sorting and assembly machinery component 50 homolog	Plays a crucial role in the maintenance of the structure of mitochondrial cristae and the proper assembly of the mitochondrial respiratory chain complexes.
ARHGEF40	Rho guanine nucleotide exchange factor 40	Acts as a guanine nucleotide exchange factor (GEF) for RHOA and RHOC.
DYSF	Dysferlin	Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion.
LEPR	Leptin receptor	Receptor for hormone LEP/leptin.
MAP4K5	Mitogen-activated protein kinase kinase kinase kinase 5	May play a role in the response to environmental stress.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 7 · Druggable fraction: 0.2

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	2.9×	0.410
Kinase	1	2.8×	0.410
Other/Unknown	7	1.2×	0.410
Scaffold/PPI	1	1.7×	0.449

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TM6SF2	Other/Unknown	no		EXPERA, TM6SF1-like, TM_Tm6sf1/2
PNPLA3	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
SUGP1	Other/Unknown	no		Surp, G_patch_dom, SWAP/Surp_sf
HSD17B13	Other/Unknown	no		SDR_fam, NAD(P)-bd_dom_sf
SAMM50	Other/Unknown	no		Bac_surfAg_D15, POTRA, D15-like
ARHGEF40	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
C1orf94	Other/Unknown	no		DUF4688
DYSF	Other/Unknown	no		C2_dom, Peroxin/Ferlin, Ferlin_A-domain
LEPR	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, Hempt_rcpt_S_F1_CS, FN3_dom
MAP4K5	Kinase	yes		Prot_kinase_dom, CNH_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

8 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
right lobe of liver	2
skeletal muscle tissue of rectus abdominis	2
duodenum	1
ileal mucosa	1
jejunal mucosa	1
pigmented layer of retina	1
lower esophagus mucosa	1
right hemisphere of cerebellum	1
right testis	1
liver	1
olfactory segment of nasal mucosa	1
endothelial cell	1
vastus lateralis	1
right adrenal gland	1
tendon of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
nasal cavity epithelium	1
sperm	1
blood	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TM6SF2	151	broad	marker	ileal mucosa, jejunal mucosa, duodenum
PNPLA3	178	ubiquitous	marker	pigmented layer of retina, buccal mucosa cell, right lobe of liver
SUGP1	262	ubiquitous	marker	lower esophagus mucosa, right testis, right hemisphere of cerebellum
HSD17B13	127	tissue_specific	yes	liver, right lobe of liver, olfactory segment of nasal mucosa
SAMM50	292	ubiquitous	marker	endothelial cell, vastus lateralis, skeletal muscle tissue of rectus abdominis
ARHGEF40	281	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, right adrenal gland
C1orf94	49	tissue_specific	yes	sperm, male germ line stem cell (sensu Vertebrata) in testis, nasal cavity epithelium
DYSF	257	ubiquitous	marker	blood, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
LEPR	272	broad	marker	trabecular bone tissue, choroid plexus epithelium, trigeminal ganglion
MAP4K5	296	ubiquitous	marker	corpus callosum, sural nerve, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSD17B13	3,393
SAMM50	2,977
LEPR	2,243
SUGP1	2,164
DYSF	1,776
PNPLA3	1,441
MAP4K5	1,055
TM6SF2	879
C1orf94	762
ARHGEF40	711

Intra-cohort edges

A	B	Sources
ARHGEF40	C1orf94	string_interaction
HSD17B13	PNPLA3	string_interaction
HSD17B13	SAMM50	string_interaction
HSD17B13	TM6SF2	string_interaction
PNPLA3	SAMM50	string_interaction
PNPLA3	TM6SF2	string_interaction
SUGP1	TM6SF2	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYSF	O75923	11
LEPR	P48357	9
SUGP1	Q8IWZ8	3
SAMM50	Q9Y512	2
HSD17B13	Q7Z5P4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TM6SF2	Q9BZW4	91.03
MAP4K5	Q9Y4K4	74.15
PNPLA3	Q9NST1	71.70
ARHGEF40	Q8TER5	64.28
C1orf94	Q6P1W5	43.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 10 evidence-associated genes (7 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lipid particle organization	1	271.9×	0.049	HSD17B13
Acyl chain remodeling of DAG and TAG	1	233.1×	0.049	PNPLA3
Signaling by Leptin	1	148.3×	0.049	LEPR
RHO GTPase cycle	2	17.2×	0.049	SAMM50, ARHGEF40
Signaling by Rho GTPases	2	9.8×	0.082	SAMM50, ARHGEF40
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	2	9.6×	0.082	SAMM50, ARHGEF40
Cristae formation	1	49.4×	0.083	SAMM50
Smooth Muscle Contraction	1	37.9×	0.085	DYSF
Cell death signalling via NRAGE, NRIF and NADE	1	31.4×	0.085	ARHGEF40
Protein localization	1	27.2×	0.085	SAMM50
p75 NTR receptor-mediated signalling	1	26.7×	0.085	ARHGEF40
NRAGE signals death through JNK	1	26.3×	0.085	ARHGEF40
Mitochondrial protein import	1	24.0×	0.085	SAMM50
Mitochondrial biogenesis	1	24.0×	0.085	SAMM50
RHOC GTPase cycle	1	20.9×	0.085	ARHGEF40
Death Receptor Signaling	1	19.9×	0.085	ARHGEF40
G alpha (12/13) signalling events	1	19.7×	0.085	ARHGEF40
RAC2 GTPase cycle	1	18.1×	0.087	SAMM50
mRNA Splicing	1	15.7×	0.095	SUGP1
mRNA Polyadenylation	1	12.6×	0.112	SUGP1
Processing of Capped Intron-Containing Pre-mRNA	1	11.7×	0.113	SUGP1
RHOA GTPase cycle	1	10.7×	0.119	ARHGEF40
Organelle biogenesis and maintenance	1	9.4×	0.128	SAMM50
mRNA Splicing - Major Pathway	1	7.8×	0.147	SUGP1
Dengue Virus-Host Interactions	1	6.5×	0.162	SUGP1
GPCR downstream signalling	1	6.2×	0.162	ARHGEF40
Signal Transduction	2	2.9×	0.162	SAMM50, ARHGEF40
Metabolism of RNA	1	6.0×	0.162	SUGP1
Signaling by GPCR	1	5.7×	0.162	ARHGEF40

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
monocyte activation involved in immune response	1	1872.4×	0.010	DYSF
triglyceride acyl-chain remodeling	1	1872.4×	0.010	PNPLA3
multicellular organism development	1	936.2×	0.010	LEPR
regulation of transport	1	936.2×	0.010	LEPR
cellular response to 3,3’,5-triiodo-L-thyronine	1	936.2×	0.010	PNPLA3
lipid homeostasis	2	74.9×	0.010	TM6SF2, PNPLA3
sexual reproduction	1	624.1×	0.013	LEPR
acylglycerol acyl-chain remodeling	1	468.1×	0.015	PNPLA3
response to sucrose	1	374.5×	0.015	PNPLA3
glycerophospholipid metabolic process	1	312.1×	0.015	PNPLA3
regulation of bone remodeling	1	312.1×	0.015	LEPR
leptin-mediated signaling pathway	1	267.5×	0.015	LEPR
response to leptin	1	267.5×	0.015	LEPR
bone growth	1	267.5×	0.015	LEPR
lipid metabolic process	2	20.4×	0.015	TM6SF2, HSD17B13
regulation of feeding behavior	1	208.1×	0.016	LEPR
protein insertion into mitochondrial outer membrane	1	144.0×	0.022	SAMM50
macrophage activation involved in immune response	1	124.8×	0.022	DYSF
energy reserve metabolic process	1	117.0×	0.022	LEPR
cristae formation	1	117.0×	0.022	SAMM50
negative regulation of phagocytosis	1	110.1×	0.022	DYSF
lipid droplet organization	1	104.0×	0.022	PNPLA3
glial cell proliferation	1	98.5×	0.022	LEPR
positive regulation of lipid biosynthetic process	1	98.5×	0.022	HSD17B13
inner mitochondrial membrane organization	1	93.6×	0.022	SAMM50
white fat cell differentiation	1	93.6×	0.022	PNPLA3
triglyceride catabolic process	1	89.2×	0.022	PNPLA3
negative regulation of gluconeogenesis	1	89.2×	0.022	LEPR
regulation of neurotransmitter secretion	1	85.1×	0.022	DYSF
triglyceride biosynthetic process	1	81.4×	0.022	PNPLA3

Therapeutics

Drugs indicated for this disease

1 approved, 14 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Resmetirom	Approved (phase 4)
Cenicriviroc	Phase 3 (in late-stage trials)
Dapagliflozin	Phase 3 (in late-stage trials)
Estradiol	Phase 3 (in late-stage trials)
Icomidocholic Acid	Phase 3 (in late-stage trials)
Lanifibranor	Phase 3 (in late-stage trials)
Losartan	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Obeticholic Acid	Phase 3 (in late-stage trials)
Pioglitazone	Phase 3 (in late-stage trials)
Rosuvastatin	Phase 3 (in late-stage trials)
Selonsertib	Phase 3 (in late-stage trials)
Semaglutide	Phase 3 (in late-stage trials)
Ubidecarenone	Phase 3 (in late-stage trials)
Vitamin E	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Atorvastatin, Betaine, Chiglitazar, Cilofexor, Digoxin, Elobixibat, Fenofibrate, Icosapent Ethyl, K-877, Leronlimab, Liraglutide, Lisinopril Anhydrous, MUROMONAB-CD3, Misoprostol, Nalmefene, Namodenoson, Norucholic Acid, Odevixibat, Pegargiminase, Pegozafermin, Pentoxifylline, Saroglitazar, Seladelpar, Sitagliptin, Solithromycin, Tirzepatide.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 4 of 10 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
MAP4K5	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP4K5	67	4
HSD17B13	1	3
TM6SF2	0	0
PNPLA3	0	0
SUGP1	0	0
SAMM50	0	0
ARHGEF40	0	0
C1orf94	0	0
DYSF	0	0
LEPR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	MAP4K5
LENVATINIB	4	MAP4K5
AXITINIB	4	MAP4K5
SORAFENIB	4	MAP4K5
NERATINIB	4	MAP4K5
PALBOCICLIB	4	MAP4K5
ENTRECTINIB	4	MAP4K5
VANDETANIB	4	MAP4K5
BOSUTINIB	4	MAP4K5
GILTERITINIB	4	MAP4K5
PAZOPANIB	4	MAP4K5
NINTEDANIB	4	MAP4K5
SUNITINIB	4	MAP4K5
DASATINIB	4	MAP4K5
QUIZARTINIB	4	MAP4K5
CRIZOTINIB	4	MAP4K5
MIDOSTAURIN	4	MAP4K5
GEFITINIB	4	MAP4K5
CILOFEXOR	3	HSD17B13
LINSITINIB	3	MAP4K5
DACTOLISIB	3	MAP4K5
CRENOLANIB	3	MAP4K5
SARACATINIB	3	MAP4K5
LINIFANIB	3	MAP4K5
CANERTINIB	3	MAP4K5
TESEVATINIB	3	MAP4K5
BRIVANIB	3	MAP4K5
BARASERTIB	3	MAP4K5
CEDIRANIB	3	MAP4K5
DOVITINIB	3	MAP4K5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MAP4K5	262	Binding:261, Functional:1
HSD17B13	22	Binding:20, Functional:2
LEPR	3	Binding:3
SAMM50	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
MAP4K5	262

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
VEMURAFENIB	4	MAP4K5
LENVATINIB	4	MAP4K5
AXITINIB	4	MAP4K5
SORAFENIB	4	MAP4K5
NERATINIB	4	MAP4K5
PALBOCICLIB	4	MAP4K5
ENTRECTINIB	4	MAP4K5
VANDETANIB	4	MAP4K5
BOSUTINIB	4	MAP4K5
GILTERITINIB	4	MAP4K5
PAZOPANIB	4	MAP4K5
NINTEDANIB	4	MAP4K5
SUNITINIB	4	MAP4K5
DASATINIB	4	MAP4K5
QUIZARTINIB	4	MAP4K5
CRIZOTINIB	4	MAP4K5
MIDOSTAURIN	4	MAP4K5
GEFITINIB	4	MAP4K5
CILOFEXOR	3	HSD17B13
LINSITINIB	3	MAP4K5
DACTOLISIB	3	MAP4K5
CRENOLANIB	3	MAP4K5
SARACATINIB	3	MAP4K5
LINIFANIB	3	MAP4K5
CANERTINIB	3	MAP4K5
TESEVATINIB	3	MAP4K5
BRIVANIB	3	MAP4K5
BARASERTIB	3	MAP4K5
CEDIRANIB	3	MAP4K5
DOVITINIB	3	MAP4K5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MAP4K5
B	Phased (≥1) drug, not yet approved	1	HSD17B13
C	Druggable family + PDB, no drug	1	LEPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	TM6SF2, PNPLA3, SUGP1, SAMM50, ARHGEF40, C1orf94, DYSF

Undrugged target profiles

8 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TM6SF2	0	HSD17B13
PNPLA3	0	HSD17B13
SUGP1	0	—
SAMM50	1	—
ARHGEF40	0	—
C1orf94	0	—
DYSF	0	—
LEPR	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 562.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	209
PHASE2	184
PHASE1	89
PHASE3	34
PHASE1/PHASE2	20
PHASE4	16
PHASE2/PHASE3	7
EARLY_PHASE1	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04639414	PHASE4	ACTIVE_NOT_RECRUITING	Combined Active Treatment in Type 2 Diabetes with NASH
NCT05195944	PHASE4	ENROLLING_BY_INVITATION	Semaglutide vs Sitagliptin
NCT06374875	PHASE4	RECRUITING	Fibrosis Lessens After Metabolic Surgery
NCT00227110	PHASE4	COMPLETED	Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)
NCT00994682	PHASE4	COMPLETED	University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)
NCT01002547	PHASE4	COMPLETED	Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Hispanics With Diabetes Mellitus Type 2 (T2DM) and Role of Treatment
NCT01269320	PHASE4	WITHDRAWN	Natural Soybean-derived Femarelle ®for Patients With Non Alcoholic Fatty Liver Disease
NCT01355575	PHASE4	TERMINATED	Rifaximin in Fatty Liver Disease
NCT01406704	PHASE4	TERMINATED	Effects of Rosiglitazone and Alpha-lipoic Acid on the Patients With Pathologically Proved NASH
NCT02210715	PHASE4	COMPLETED	Raltegravir-based Antiretroviral Versus Maintaining Any Other Antiretroviral Therapy in HIV Mono-infected Patients
NCT03198572	PHASE4	UNKNOWN	Efficacy and Safety of Berberine in Non-alcoholic Steatohepatitis
NCT03648554	PHASE4	UNKNOWN	Researching an Effect of GLP-1 Agonist on Liver STeatosis (REALIST)
NCT03950505	PHASE4	UNKNOWN	To Evaluate the Effect of Nesinaact on Non-alcoholic Steatohepatitis Through MRI and Liver Fibroscan in Patients With Type 2 Diabetes
NCT04537780	PHASE4	COMPLETED	Efficacy and Safety of Montelukast in Non Alcoholic Steatohepatitis (NASH)
NCT04976283	PHASE4	UNKNOWN	Effect of Oral Anti-diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non-alcoholic Fatty Liver
NCT04977661	PHASE4	COMPLETED	Comparing the Effects of Vitamin E, Ursodeoxycholic Acid and Pentoxyfylline on Egyptian Non-alcoholic Steatohepatitis (NASH) Patients
NCT03900429	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study to Evaluate the Efficacy and Safety of MGL-3196 (Resmetirom) in Patients With NASH and Fibrosis
NCT04822181	PHASE3	ACTIVE_NOT_RECRUITING	Research Study on Whether Semaglutide Works in People With Non-alcoholic Steatohepatitis (NASH)
NCT04833140	PHASE3	RECRUITING	Estrogen Administration for the Treatment of NASH in Postmenopausal Women
NCT04849728	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Evaluating Efficacy and Safety of Lanifibranor Followed by an Active Treatment Extension in Adult Patients With (NASH) and Fibrosis Stages F2 and F3 ( NATiV3 )
NCT05500222	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study to Evaluate the Effect of Resmetirom on Clinical Outcomes in Patients With Well-compensated NASH Cirrhosis (MAESTRO-NASH-OUTCOMES)
NCT06161571	PHASE3	ACTIVE_NOT_RECRUITING	A Study Evaluating Efruxifermin in Subjects With Non-invasively Diagnosed Nonalcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Nonalcoholic Fatty Liver Disease (NAFLD)/Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
NCT06528314	PHASE3	RECRUITING	A Study Evaluating Efruxifermin in Subjects With Compensated Cirrhosis Due to NASH/MASH
NCT06632444	PHASE3	RECRUITING	LIVERAGE™: A Study to Test Whether Survodutide Helps People With a Liver Disease Called NASH/MASH Who Have Moderate or Advanced Liver Fibrosis
NCT06632457	PHASE3	RECRUITING	LIVERAGE™ - Cirrhosis: A Study to Test Whether Survodutide Helps People With a Liver Disease Called NASH/MASH Who Have Cirrhosis
NCT07581951	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study Evaluating the Safety and Efficacy of HSK31679 in Patients With MASH
NCT00267670	PHASE2/PHASE3	COMPLETED	Pentoxifylline/Nonalcoholic Steatohepatitis (NASH) Study: The Effect of Pentoxifylline on NASH
NCT00509418	PHASE3	COMPLETED	Efficacy and Safety of Viusid in Patients With Nonalcoholic Steatohepatitis
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT00681408	PHASE2/PHASE3	COMPLETED	Omega 3 Fish Oil Supplements vs. Placebo for Patients With Non-alcoholic Steatohepatitis (NASH)
NCT00820651	PHASE3	COMPLETED	Efficacy and Safety of Diamel in Patients With Nonalcoholic Steatohepatitis
NCT01051219	PHASE3	COMPLETED	Anti-Fibrotic Effects of Losartan In Nash Evaluation Study
NCT01384578	PHASE3	WITHDRAWN	Pentoxiphylline and Vitamin E Versus Vitamin E in Patients With Non- Alcoholic Steatohepatitis
NCT01791959	PHASE2/PHASE3	COMPLETED	The Effects of Synbiotics Supplement on Biochemical Factors and Hepatic Fibrosis in Patients With Nonalcoholic Steatohepatitis
NCT02098317	PHASE3	COMPLETED	DHA and Vitamin D in Children With Biopsy-proven NAFLD
NCT02395900	PHASE2/PHASE3	COMPLETED	The Effects of Flaxseed Supplement on Biochemical Factors and Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
NCT02530138	PHASE2/PHASE3	UNKNOWN	The Effect of Synbiotics Supplement on Lipid Profile, Liver Enzymes, Inflammatory Factors and Hepatic Fibrosis in Lean and Normal Weight Patients With Nonalcoholic Fatty Liver
NCT02541045	PHASE3	WITHDRAWN	Clinical Trial to Evaluate the Efficacy of Metadoxine as a Therapy for Patients With Non-alcoholic Steatohepatitis
NCT02548351	PHASE3	TERMINATED	Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of Obeticholic Acid Treatment
NCT02654665	PHASE3	UNKNOWN	Comparing Effects of Liraglutide and Bariatric Surgery on Weight Loss, Liver Function, Body Composition, Insulin Resistance, Endothelial Function and Biomarkers of Non-alcoholic Steatohepatitis (NASH) in Obese Asian Adults

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PIOGLITAZONE	4	7
VITAMIN E	4	5
OBETICHOLIC ACID	4	4
RESMETIROM	4	4
URSODIOL	4	4
BERBERINE	4	3
DIOSMIN	4	3
PENTOXIFYLLINE	4	3
DIGOXIN	4	2
ELAFIBRANOR	4	2
METFORMIN	4	2
METRELEPTIN	4	2
ROSIGLITAZONE	4	2
SEMAGLUTIDE	4	2
TESAMORELIN	4	2
BETAINE	4	1
COLESEVELAM HYDROCHLORIDE	4	1
DEFERASIROX	4	1
ELTROMBOPAG	4	1
EMPAGLIFLOZIN	4	1
ETHINYL ESTRADIOL	4	1
FLUVOXAMINE	4	1
FLUVOXAMINE MALEATE	4	1
GLUCAGON	4	1
IDEBENONE	4	1
LEVOCARNITINE	4	1
LEVONORGESTREL	4	1
LEVOTHYROXINE SODIUM	4	1
LISINOPRIL	4	1
LISINOPRIL ANHYDROUS	4	1