Cholestatic liver injury, marked by impaired bile flow, toxic bile acid accumulation, inflammation, and hepatocellular damage, often progresses to fibrosis, cirrhosis, and cancer. First‑line therapy with ursodeoxycholic acid (UDCA) fails in up to 40% of patients, creating an urgent need for novel targets and treatments. Hepatic iNKT cells shape inflammatory outcomes: pathogenic iNKT17 cells drive cholestatic injury, while protective iNKT1 cells resolve inflammation, but how to therapeutically tune this balance has remained unknown.
A research team led by Prof. Xinzhi Wang, Prof. Jun Liu, and Prof. Mengtao Xing from China Pharmaceutical University has uncovered a central immune mechanism: CTSS acts as a molecular switch governing iNKT cell polarization via autophagy. In cholestasis, iNKT‑derived CTSS is sharply upregulated, suppressing autophagy/mitophagy and locking iNKT cells into a pro‑inflammatory iNKT17 phenotype that amplifies liver damage.
The team shows that celastrol, a widely studied natural triterpenoid, acts via a dual mechanism:
Celastrol directly binds and inhibits CTSS (SPR, molecular docking).
Inhibition of CTSS restores autophagic flux and mitophagy in iNKT cells, marked by reduced p62, elevated LC3‑II/I, Parkin, and PINK1.
This rewires iNKT cell fate: celastrol robustly shifts the balance from IL‑17‑producing iNKT17 to IFN‑γ‑producing iNKT1 cells, both in vivo (EE‑ and ANIT‑induced cholestasis models) and in hepatocyte–iNKT co‑cultures.
Functional validation confirms this axis is essential:
CTSS inhibition (pharmacological or genetic) mimics celastrol’s protection.
CTSS overexpression or autophagy blockade (chloroquine) abolishes celastrol’s benefits.
In CTSS‑knockout mice, celastrol no longer induces iNKT1 polarization or alleviates cholestasis.
CD1d‑deficient mice (lacking iNKT cells) abolish cholestasis‑induced CTSS upregulation, proving iNKT cells are the primary source of pathological CTSS.
Clinically relevant findings include:

CTSS mRNA is markedly elevated in peripheral blood mononuclear cells (PBMCs) from patients with intrahepatic cholestasis of pregnancy (ICP).
Celastrol normalizes bile acid homeostasis via FXR–CYP/Bsep/NTCP signaling and reduces serum ALT/AST/ALP, liver necrosis, inflammatory infiltration, and ductular proliferation.
Celastrol also mitigates CCl₄‑induced liver fibrosis by suppressing HSC activation (α‑SMA, collagen I) through the same CTSS–autophagy–iNKT1 axis.
These results establish CTSS as a novel therapeutic target for cholestatic liver disease and validate celastrol as a promising immune‑modulating candidate that safely reprograms iNKT cells toward a protective phenotype.
This work entitled “Celastrol ameliorates cholestatic liver injury by promoting a protective iNKT1 polarization via CTSS inhibition and autophagy restoration” was published online April 29, 2026, in Targetome.

DOI: 10.48130/targetome-0026-0018