β-Caryophyllene protects male fertility and testicular function against paclitaxel-induced damage in a murine model

β-Caryophyllene (BCP) is a naturally occurring dietary sesquiterpene found in various edible plants and spices, such as clove, black pepper, and cinnamon, and is noted for its strong antioxidant and anti-inflammatory effects. Nevertheless, its preventive function against chemotherapy-induced male reproductive damage has not been sufficiently investigated. This study examined the functional dietary potential of BCP in alleviating paclitaxel (PTX)-induced testicular damage and explained its underlying molecular mechanisms. Five groups of male rodents were randomly assigned: control, BCP alone, PTX, PTX + BCP (low dose), and PTX + BCP (high dose). We assessed oxidative stress markers in the testicles and used Western blotting to examine the protein levels of p-AMPK, SIRT3, Nrf2, and markers of apoptosis. Histopathological changes, collagen accumulation, and apoptotic cell death were assessed via hematoxylin-eosin, Masson's trichrome, and TUNEL tests, respectively. PTX administration significantly altered testicular homeostasis, as indicated by inhibited p-AMPK/SIRT3/Nrf2 signaling, reduced antioxidant enzyme activities, heightened lipid peroxidation and oxidative DNA damage, increased proinflammatory cytokines, and augmented apoptosis. These molecular alterations were associated with significant histological deterioration, excessive collagen accumulation, diminished serum testosterone concentrations, decreased testicular coefficient, and compromised sperm quality. Notably, BCP co-treatment dose dependently restored antioxidant capacity, reactivated p-AMPK/SIRT3/Nrf2 signaling, suppressed inflammatory and apoptotic responses, and protected testicular architecture and reproductive function. BCP alone did not cause any bad effects. β-Caryophyllene, a bioactive dietary ingredient, demonstrates substantial protective benefits against PTX-induced testicular toxicity through the activation of the p-AMPK/SIRT3/Nrf2 pathway. These results underscore BCP as a viable functional food-derived adjuvant for ameliorating chemotherapy-induced male reproductive failure.