# L-cysteine mitigates busulfan-induced testicular injury through modulation of CBS/H2S axis

## TL;DR

L-cysteine helps protect against testicular damage caused by busulfan by boosting hydrogen sulfide production and reducing oxidative stress and cell death.

## Contribution

The study reveals that L-cysteine protects against busulfan-induced testicular injury via the CBS/H2S axis and PI3K/Akt/mTOR pathway activation.

## Key findings

- L-cysteine improves body weight, testis weight, sperm count, and motility in busulfan-treated mice.
- L-cysteine reduces oxidative stress and apoptosis through Nrf2/HO-1 and PI3K/Akt/mTOR pathways.
- The protective effects of L-cysteine are reversed by the CBS inhibitor AOAA, confirming the role of the CBS/H2S axis.

## Abstract

Global male infertility, characterized by decreased spermatogenesis and sperm quality, is a significant concern. L-cysteine, essential for hydrogen sulfide (H2S) synthesis, offers numerous biological advantages. However, the protective mechanisms of L-cysteine in treating spermatogenic dysfunction need further exploration. This study aims to examine L-cysteine’s protective effects on busulfan-induced testicular toxicity. Results show that administering L-cysteine at different doses (2.5, 5.0, and 10 mg/kg) led to notable improvements in final body weight, testis weight, sperm count, sperm motility, testosterone levels, and seminiferous tubule architecture. At a 5.0 mg/kg dosage, L-cysteine mitigated testicular injury by activating the CBS/H2S axis. Moreover, L-cysteine effectively reduced apoptosis and oxidative stress through Nrf2/HO-1 pathway activation. Various analyses demonstrated that L-cysteine enhanced the repair of the blood-testis barrier (BTB) disrupted by busulfan. Mechanistically, L-cysteine activated the PI3K/Akt/mTOR pathway in the testes. Notably, the CBS inhibitor AOAA reversed L-cysteine’s protective effects on busulfan-induced testicular damage. In summary, the study suggests that L-cysteine can safeguard against busulfan-induced spermatogenic dysfunction, apoptosis, oxidative stress, and BTB disruption by modulating the PI3K/Akt/mTOR pathway, hinging on CBS/H2S axis activation. These findings propose L-cysteine as a potential treatment for male infertility, particularly in individuals undergoing busulfan chemotherapy.

Diagram showing a mouse injected with Busulfan, leading to oxidative stress, ROS production, and apoptotic pathways involving Bcl-2, Bax, Cyto C, and Caspase-3. L-cysteine and CBS produce H2S, which counteracts ROS. The PI3K pathway involving Akt and mTOR, as well as BTB disruption, are depicted.