Tehran University of Medical Sciences Iranian Journal of Parasitology 1735-7020 21 2 2026 07 12 185 194 Maryam khodadadi School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran Mohammad Javad Pour Maram Department of Parasitology, School of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran Hossein Amini Khoei Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran Hadi Raeisi Shahraki Department of Biostatistics, Shahrekord University of Medical Sciences, Shahrekord, Iran Ebrahim Saedi Dezaki Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran 2025 09 09 2026 07 12 Background: Natural compounds have garnered increasing attention as candidate antiparasitic therapeutics. We aimed to evaluate the protoscolicidal efficacy of caryophyllene (CAP), alone and in combination with albendazole (ALZ), against hydatid cyst protoscoleces. Methods: Suspensions of 10,000 invaginated and evaginated protoscoleces (400 µL normal saline) were exposed to CAP (62.5–500 µg/mL), ALZ (250 µg/mL), or CAP+ALZ combinations in 24-well culture plates. Protoscolex viability was assessed by eosin exclusion test. Reactive oxygen species (ROS) induction was quantified using the DCFH-DA assay, and pre-apoptotic gene expression was analyzed by real-time PCR. Results: CAP, particularly in combination with ALZ, significantly reduced the viability of both invaginated and evaginated protoscoleces in a concentration- and time-dependent manner. Combination therapy achieved 100% mortality of invaginated protoscoleces within 10–30 minutes, demonstrating significant synergism over either monotherapy. Evaginated protoscolex viability was also markedly diminished. The observed scolicidal activity was mechanistically correlated with apoptosis induction, evidenced by elevated ROS production and significant upregulation of caspase-3 and P53 gene expression (P<0.001). Conclusion: CAP, particularly in combination with ALZ, exhibits potent in vitro protoscolicidal activity against hydatid cyst protoscoleces, with apoptosis induction and ROS generation implicated as underlying mechanisms. Further pharmacodynamic investigations and clinical trials are warranted to elucidate the precise mechanisms of action and evaluate the therapeutic potential of CAP-based combination therapy in the management of cystic echinococcosis. https://ijpa.tums.ac.ir/index.php/ijpa/article/view/4761 https://ijpa.tums.ac.ir/index.php/ijpa/article/download/4761/1493