The fallopian tube is an essential component of the mammalian reproductive system, serving a vital function in the transport of gametes and the initial development of embryos(Sahin et al., 2018). Salpingitis, a form of pelvic inflammatory disease (PID), is a prevalent gynecological condition characterized by infection in the upper genital tract(Soper, 2010). Etiological factors contributing to salpingitis include gynecological laparoscopy, surgical procedures, induced abortion, and endometriosis(Wiesenfeld et al., 2002). The primary causative pathogens of salpingitis commonly include mycoplasma, chlamydia, and bacterial infections(Cohen et al., 2005; Shao et al., 2012; Yao et al., 2020). Salpingitis has been associated with tubal occlusion and hydrosalpinx, which can lead to ectopic pregnancy and infertility. Tubal factor infertility is a prevalent cause of female infertility, representing 25 %–35 % of cases(Lim et al., 2015). Tubal damage resulting from salpingitis is a significant etiological factor in ectopic pregnancy, accounting for over 90 % of cases(Gynecologists, 2018). Currently, the primary approach to treating salpingitis involves fallopian tube recanalization, with medication options including antibiotics, enzyme drugs, and adrenocortical hormone drugs(Zhang et al., 2022). However, there is a high risk of relapse, significant adverse reactions, and dependence upon cessation of drug therapy. Consequently, there is a critical necessity for the development of novel targeted therapies to enhance the effectiveness of salpingitis treatment.

Necroptosis, a non-apoptotic form of cell death, is implicated in various inflammatory conditions and related diseases(Weinlich et al., 2017). The mechanism of necroptosis involves receptor-interacting serine/threonine-protein kinase 3 (RIPK3) as a downstream target of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), with RIPK1 kinase activating RIPK3 to phosphorylate and activate mixed lineage kinase domain-like protein (MLKL)(Kolbrink et al., 2023). In contrast to apoptosis, necroptosis is characterized by the release of cellular contents and the initiation of an inflammatory response(Pasparakis and Vandenabeele, 2015). Recent research has highlighted necroptosis as a significant contributor to the pathogenesis of inflammatory diseases, including hepatic inflammation, lung injury, and cerebral injury(Gautam et al., 2024; Shen et al., 2024; Yu et al., 2024). To date, limited research has been conducted on the role of necroptosis in salpingitis-induced infertility and PID(Li et al., 2023). Previous studies have suggested that endoplasmic reticulum stress can trigger necroptosis in granulosa cells, resulting in premature ovarian failure and female infertility(Li et al., 2023). Additionally, recent research has demonstrated that bilateral varicocele can induce necroptosis in human spermatozoa, impacting semen quality in infertile males(Sun et al., 2023). These findings suggest that necroptosis may serve as a significant mechanism in the pathogenesis of salpingitis.

The cytoprotective transcription factor nuclear factor E2-related factor-2 (Nrf2) has been shown to regulate antioxidative genes and modulate necroptosis(S. Li et al., 2024). Additionally, Nrf2 has been implicated in PID and infertility(Pal et al., 2023). In a hamster model of bisphenol S-induced ovarian dysfunction, melatonin was found to stimulate key redox/survival markers, including silent information regulator of transcript-1 (SIRT-1), Forkhead box protein O1 (FOXO-1), and Nrf2, leading to enhanced ovarian antioxidant capacity(Pal et al., 2023). Luteolin has been shown to prevent S. aureus-induced disruption of the endometrial barrier by up-regulating the expression of Nrf2 and heme oxygenase-1 (HO-1), thereby contributing to the attenuation of PID(Gao et al., 2024). Previous research has indicated that the Nrf2 pathway is capable of interacting with neurogenic locus notch homolog receptor-1 (Notch1) signaling. Notch1 has been found to facilitate the interaction between recombination signal binding protein for immunoglobulin Kappa J region (RBPjκ) and Nrf2, while disruption of the Notch1 signal in phosphatase and tensin homolog (PTEN) deletion macrophages has been shown to reduce RBPjκ and Nrf2 binding(Yang et al., 2023). In blastocysts from pregnant mice, microinjection of Nrf2 shRNA has been found to significantly decrease Notch1 mRNA levels, leading to apoptosis(YM. Li et al., 2024). Moreover, numerous studies have suggested that the Notch1 signaling pathway plays a crucial role in gynecological diseases(Parambath et al., 2024). Excessive activation of Notch1 signaling has been shown to enhance the proliferative capacity of luminal and glandular epithelial cells, while also diminishing the transcriptional distinctions between them, indicating a disturbance in the differentiation of uterine epithelial cells(Xu et al., 2023). A prior investigation demonstrated that the uterine-specific hyperactivation of canonical Notch1 signaling in mice leads to infertility due to various developmental and physiological abnormalities, as well as heightened collagen deposition(Xu et al., 2021). These findings suggest that Nrf2 and Notch signaling pathways could be involved in modulating cellular inflammation and may represent a potential therapeutic target for salpingitis.

Chicoric acid, a polyphenolic acid compound, is commonly found in various edible plants and vegetables such as Cichorium intybus, Echinacea pallida, and Taraxacum officinale(Goyal et al., 2024). It exhibits antiviral, anti-inflammatory, neuroprotective, and antioxidative properties(Di et al., 2024; Kevrekidou et al., 2024; Tráj et al., 2022; Wang et al., 2024). A previous study has elucidated the additional therapeutic benefits of chicoric acid in the treatment of PID(Wang et al., 2022). Chicoric acid was found to effectively inhibit ferroptosis in lipopolysaccharide (LPS)-induced endometritis and upregulate the expression of Nrf2 and HO-1(Wang et al., 2022, Wang et al., 2022, Wang et al., 2022). Furthermore, the inhibitory effects of chicoric acid on LPS-induced endometritis and ferroptosis were significantly attenuated in Nrf2 knockdown mice(Wang et al., 2022). In the context of chronic inflammatory diseases, the roles of chicoric acid have been documented(Di et al., 2024). It was demonstrated that chicoric acid induced a notable reduction in dextran sulfate sodium (DSS) induced colitis through the activation of Nrf2 and its associated antioxidant molecules, as well as the suppression of inflammation and apoptosis pathways linked to colitis progression(Di et al., 2024). Nevertheless, the precise functions of chicoric acid and its underlying mechanism in salpingitis treatment remain ambiguous. This study sought to explore the role of chicoric acid in salpingitis and elucidate its specific mechanism of action.