Depression is a leading contributor to global mental and physical impairment, and a key component of the global disease burden (Dugani et al., 2018). Ranked as the third top cause of disability-adjusted life years, depression accounts for approximately 25 % of all mental disorder instances (GBD, 2019 Mental Disorders Collaborators, 2022). The current first-line antidepressants primarily modulate the monoaminergic system, and their clinical utility remains limited by several factors, including delayed onset of therapeutic effects, treatment resistance, and insufficient efficacy for reducing suicide risk (Malhi et al., 2018; Trivedi et al., 2006). Additionally, long-term administration of selective serotonin reuptake inhibitors is linked to notable side effects, including sexual dysfunction, sleep disturbances, and pregnancy-related complications (Moret et al., 2009; Sun et al., 2022). These limitations underscore the pressing demand for alternative antidepressants with improved efficacy and safety profiles, emphasizing the clinical and public health significance of this research.

Researchers have increasingly acknowledged mitochondrial dysfunction as a key determinant of depression development, wherein compromised mitophagy acts as a major pathogenic mechanism (Zhang et al., 2024; Ge et al., 2025; Scaini et al., 2022). Mitophagy eliminates damaged mitochondria via autophagosome-lysosome degradation though a selective autophagy process (Lu et al., 2023). The canonical PINK1/Parkin pathway serves as the principal regulatory machinery (Jin et al., 2022). Specifically, mitochondrial depolarization triggers PINK1 accumulation on the outer mitochondrial membrane. This then recruits cytoplasmic Parkin to the damaged mitochondria. Subsequently, Parkin undergoes activation and mediates ubiquitination of mitochondrial proteins. These ubiquitinated substrates are recognized by p62/SQSTM1, a molecule that targets damaged components to phagophores through specific binding to LC3-II (a phagophore membrane marker). This process leads to autophagosome maturation (Ashrafi et al., 2013; Malpartida et al., 2021; Pickrell et al., 2015; Geisler et al., 2010). Sirtuin 3 (SIRT3) functions as an NAD+-dependent deacetylase primarily localized to the mitochondrial matrix and inner membrane (Ning et al., 2024). It serves a crucial function in sustaining mitochondrial homeostasis by modulating oxidative stress, energy metabolism, and biogenesis (Wang et al., 2022). Studies have indicated that SIRT3 activates the PINK1/Parkin pathway to promote mitophagy, thereby ameliorating mitochondrial dysfunction (Deng et al., 2025). However, the precise mechanistic link between the SIRT3-mediated regulation of PINK1/Parkin-dependent mitophagy and its therapeutic potential for mitigating mitochondrial damage in depression remains unclear.

Chuanxiong (the rhizomes of Ligusticum chuanxiong Hort.) was first described in the Shennong Bencao Jing. In traditional Chinese medicine (TCM), it is primarily used to promote blood circulation and resolve Qi stagnation. For the purpose of treating depression, it has been historically employed as a key component in herbal formulas including Yueju Wan and Chaihu Shugan San. According to TCM theory, the smooth flow of Qi and blood is fundamental to emotional stability. This principle underpins the traditional use of Chuanxiong in mood regulation, thus forming the rationale for investigating its antidepressant effects (Chen et al., 2018; Xing et al., 2024; Qin et al., 2022). Phthalides are the characteristic and bioactive components of L. chuanxiong, and they have drawn considerable research interest due to their unique structural features and potential in drug discovery. A prime example is butylphthalide. It is derived from Apium graveolens Linn, and has been successfully developed into a clinical drug for the adjunctive therapy of ischemic stroke (Wang et al., 2023). Growing evidence has demonstrated that butylphthalide exerted mitochondrial protective effects across multiple disease models. It suppressed mitochondrial DNA release and ROS generation via the cGAS-STING pathway in Parkinson's models (Liu et al., 2024b), regulated mitophagy through PINK1/Parkin in myocardial ischemia-reperfusion injury (Zhao et al., 2024b), and maintained mitochondrial function by inhibiting Drp1 acetylation in cerebral ischemic damage (Zhang et al., 2025). Another phthalide analog, ligustilide, has been shown to mitigate cerebral ischemic injury by activating AMPK and promoting Drp1-mediated mitochondrial fission (Wu et al., 2022), and to reduce oxidative stress during renal ischemia-reperfusion by maintaining SIRT3-dependent mitochondrial homeostasis (Xia et al., 2024). Among these phthalides, LA is a characteristic and active phthalide dimer of Chuanxiong (Fig. 1) that has emerged as a promising candidate for neurological diseases (Ni et al., 2023; Zhang et al., 2024b). Its structural analogs have already demonstrated direct regulatory effects on mitochondrial pathways. Based on these findings, we hypothesized that LA alleviated depression and anxiety by modulating the SIRT3/PINK1/Parkin pathway. Therefore, we utilized LPS-induced in vivo and in vitro depression and anxiety models to systematically explore the therapeutic effects and underlying mechanism of LA.