Gout, a prevalent inflammatory joint disease, primarily results from the deposition of monosodium urate (MSU) in the joints, leading to a cascade of inflammatory reactions within the joint cavity (Bodofsky et al., 2020; Chen et al., 2017). Hyperuricemia, characterized by abnormally high levels of uric acid in the bloodstream, often accompanies gout and is considered a risk factor for gout attacks (Helget and Mikuls, 2022). Asymptomatic hyperuricemia can progress to gouty arthritis in some cases (Chilappa et al., 2010; Copur et al., 2022). The prevalence of gout has been steadily increasing in recent years, becoming a significant global health concern. In 2019, China alone reported a staggering 16.2 million gout cases, representing a prevalence rate of 16.2 per 1000 people and accounting for nearly a third of all cases worldwide (Zhang et al., 2023; Zhu et al., 2022). Alarmingly, gout is no longer just a disease of the elderly, with a growing number of young people being diagnosed. Globally, in 2019, an estimated 780,000 individuals under the age of 29 suffered from gout, constituting almost 15% of all patients (Zhang et al., 2023). This surge in cases has established gout as the second most common metabolic disorder, following closely behind diabetes (Zhu et al., 2021).

Clinical management of hyperuricemia in asymptomatic patients involves the use of allopurinol and febuxostat to lower blood uric acid levels, to aim at preventing the onset of gout. For patients already experiencing gouty arthritis, non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine are commonly administered to suppress inflammatory factors in the joint capsule and alleviate gout symptoms (Ashiq et al., 2021; Hainer et al., 2014; van Echteld et al., 2014). However, these Western drugs, while effective, often carry irreversible adverse effects. Allopurinol, for example, can cause eosinophilia and systemic symptoms, potentially leading to allopurinol hypersensitivity syndrome in patients with chronic kidney disease, which can be life-threatening in severe cases (Stamp et al., 2016). Similarly, colchicine, widely used for gout treatment, has a narrow therapeutic index, unknown toxicity in high doses, and can result in multi-organ failure if ingested inappropriately, leading to high mortality rates (Finkelstein et al., 2010). NSAIDs have also been associated with various organ pathologies such as gastrointestinal complications, cardiovascular disease, kidney damage, and hepatotoxicity (Bindu et al., 2020). Consequently, developing safer and more effective anti-gout drugs is a major focus in current gout research. Traditional Chinese medicine is relatively safe and has few side effects, providing a potential way to explore the therapeutic effect of gout.

Many herbal medicines, such as extracts from Reynoutria japonica Houtt. (Huzhang), celery seed, Cichorium intybus L. (Juju), have demonstrated effectiveness in treating gout (Li et al., 2019; Ma et al., 2019; Wang et al., 2019). Among these potential remedies, Piper longum L. (PL) (Biba), a plant belonging to the Piperaceae family with a long history in traditional medicine, stands out. Used in Traditional Chinese and Tibetan Medicine, PL is considered safe for consumption. Studies have confirmed its low toxicity, even at high doses, with no significant adverse effects on organs or body weight in mice (Biswas et al., 2022).

PL's traditional uses often focus on joint pain and inflammation. According to the “Four Medical Classics”, in Tibetan medicine, PL is boiled with water and drunk to treat gout. As recorded in “Tian bao Ben Cao”, PL can be used to treat joint injuries and relieve joint pain. Tibetan medicine utilizes it for gout treatment, while Traditional Chinese Medicine combines its fruit spikes with the tuberous roots of Aconitum kusnezoffii Rchb. (Caowu) and the fruits of Terminalia chebula Retz. (Hezi) to address rheumatism and arthritis (Liu, 2022). Modern research supports these applications, highlighting PL's ability to: (1) Reduce inflammation: PL extract has shown efficacy in inhibiting inflammation caused by lipopolysaccharide (LPS) in cells and carrageenan in rats. It achieves this by decreasing the production of inflammatory markers like TNF-α, NO, and IL-6. (Gao et al., 2023; Kumar et al., 2009; Phan et al., 2024). (2) Alleviate joint pain: PL's impact on synovial cell apoptosis suggests its potential in managing joint inflammation and pain (Cai et al., 2012). Research has identified numerous compounds in PL, including piperine, pipernonaline, and various alkaloids, many exhibiting strong anti-inflammatory activity. Piperine and pipernonaline, in particular, demonstrate potent anti-inflammatory effects (Guo et al., 2019; Wan et al., 2023). While the existing research paints a promising picture of PL's therapeutic potential for gout, further investigation is needed. Detailed studies specifically focusing on PL's efficacy in treating gout are crucial to fully understand its benefits and establish optimal usage guidelines.

This study aimed to explore the potential of 70% ethanolic extract of PL fruiting spike as an anti-gout treatment. We employed various techniques, including UPLC-Q/TOF-MS, network pharmacology, and molecular docking, to elucidate the mechanism of action of PL. To further confirm the accuracy of the above research results, we also used the air pouch inflammation model and hyperuricemia model to confirm the pharmacological effects and mechanisms of PL. In conclusion, this study lays a solid foundation for future studies on the efficacy of PL in gout treatment.