Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.

BACKGROUND

Cancer cachexia is a debilitating syndrome characterized by severe skeletal muscle wasting, which significantly impairs patient quality of life and survival. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in tryptophan (Trp) metabolism, is often upregulated in cancers, but its specific role in driving lung cancer-associated cachexia remains inadequately defined.

This study investigated the mechanistic role of Ido1 in cancer cachexia and evaluated the therapeutic potential of its inhibition.

METHODS

We established Lewis lung carcinoma (LLC) models in C57BL/6 mice using wild-type, Ido1-overexpressing (Ido1-OE) and Ido1-knockout (Ido1-KO) cells. Muscle mass, tumour growth and metabolic changes were assessed in vivo.

Transcriptomic and targeted metabolomic analyses were performed on muscle and serum samples. In vitro, we examined the effects of tumour-conditioned media, the Trp metabolite kynurenine (Kyn) and Trp supplementation on C2C12 myotube atrophy.

In vivo experiments verified the efficacy of the Ido1 inhibitor palmatine hydrochloride (PAL). Molecular pathways were analysed via western blot and qPCR.

RESULTS

Compared to LLC mouse models, Ido1-OE significantly exacerbated tumour growth and cachexia, leading to a significant decrease in lean body weight, gastrocnemius and tibialis anterior muscle weights (p < 0.01, p < 0.0001, p < 0.001).

Gastrocnemius muscle fibre cross-sectional area significantly decreased in the Ido1-OE group (p < 0.0001). Transcriptomic analysis revealed that Ido1-OE activated pro-inflammatory and protein degradation pathways (upregulating MuRF1/Atrogin1, p < 0.05) while suppressing anabolic signalling pathways (oestrogen pathways, p < 0.01).

Metabolomics analysis revealed unique metabolic signatures in Ido1-OE mice: Trp depletion and Kyn accumulation. In vitro experiments demonstrated that Ido1-OE enhanced LLC cell proliferation and migration capabilities (p < 0.0001, p < 0.0001).

Tumour-conditioned medium (TCM) derived from Ido1-OE tumours significantly induced C2C12 myotube atrophy (p < 0.01). Similarly, direct treatment with Kyn led to dose-dependent muscle fibre shrinkage, with significant atrophy observed at 30 μM (p < 0.01) and 100 μM (p < 0.0001).

Notably, the myotube atrophy induced by Kyn was significantly reversed by the addition of supplemental Trp (p < 0.0001). Compared with the Ido1-OE group, PAL treatment reduced gastrocnemius and tibialis anterior atrophy (p < 0.01; p < 0.05).

Mechanistically, PAL inhibited the mRNA expression levels of MuRF1/Atrogin1 (p < 0.0001, p < 0.001), as well as their corresponding protein levels (p < 0.0001, p < 0.0001). Furthermore, PAL restored the phosphorylation level of mTOR (p < 0.001), as well as the mRNA expression of myosin heavy chain (p < 0.01).

CONCLUSIONS

Our findings demonstrate that Ido1 accelerates muscle atrophy and cancer cachexia by driving a metabolic reprogramming centred on the Trp-Kyn pathway.

Pharmacological inhibition of Ido1 with PAL effectively mitigates these effects, positioning Ido1 as a promising therapeutic target for treating cancer cachexia.