Targeting TLR4/NF-κB signaling, oxidative stress, and apoptosis by farnesol mitigates cadmium-induced testicular toxicity in rats

Hassanein, EHM ORCID: https://orcid.org/0000-0003-4865-2342, Alotaibi, MF, Alruhaimi, RS, Sabry, M, Sayed, GA, Atwa, AM and Mahmoud, AM ORCID: https://orcid.org/0000-0003-0279-6500 (2025) Targeting TLR4/NF-κB signaling, oxidative stress, and apoptosis by farnesol mitigates cadmium-induced testicular toxicity in rats. Tissue and Cell, 94. 102813. ISSN 0040-8166

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Abstract

Cadmium (Cd) is a highly toxic heavy metal, and its detrimental effects on reproductive health pose a significant risk to the general population. Farnesol (FAR), a sesquiterpene alcohol, exhibits anti-inflammatory, antioxidant, and anticancer properties. This study investigated the protective effects of FAR against Cd-induced testicular toxicity, focusing on its antioxidant and anti-inflammatory mechanisms. Rats were randomly divided into four experimental groups: control, FAR (10 mg/kg), Cd (1.2 mg/kg), and Cd + FAR. Cd administration caused testicular tissue damage, altered hormone levels, oxidative stress and apoptosis, upregulated TLR4/NF-κB signaling and diminished antioxidants. FAR ameliorated gonadotropins and testosterone, prevented tissue damage, and attenuated oxidative stress. Additionally, FAR significantly attenuated the inflammatory response triggered by Cd, as evidenced by reduced levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and suppression of the TLR4/NF-κB signaling pathway. FAR inhibited testicular apoptosis by upregulating the anti-apoptotic protein Bcl-2 and downregulating the pro-apoptotic markers Bax and caspase-3. These results suggest that FAR mitigates Cd-induced testicular toxicity through upregulation of antioxidants, suppression of TLR4/NF-κB signaling, and inhibition of apoptotic pathways. Thus, FAR represents a promising therapeutic agent for protecting against Cd-induced reproductive damage.