The Extract of <em>Polygonum capitatum</em> Alleviates Hyperoxaluria-Induced Oxidative Stress by Targeting the PI3K-ERK-NRF2 Signaling Pathway.

<em>Persicaria capitata </em>(Buch.-Ham. ex D. Don) H. Gross is a perennial herb belonging to the Polygonaceae family, mainly distributed in southwestern China. <em>Persicaria capitata </em>is edible and boasts a high nutritional profile, and the entire plant serves medicinal purposes. According to the <em>Guangxi Materia Medica</em>, it has the functions of "relieving wind-dampness, enhancing blood circulation, and easing pain". <em>Persicaria capitata </em>is a major component of the traditional Chinese medicine formula, Re-Lin-Qing, which is widely used for treating urinary calculi (urolithiasis). However, its specific mechanisms of action remain unclear. In this study, we employed molecular biology, molecular dynamics, and cellular biology strategies to develop a rat experimental model of oxalate-induced urolithiasis and a cell model of oxalate-induced injury to study the active constituents and molecular mechanisms of <em>Persicaria capitata </em>in inhibiting oxalate stone formation both in vivo and in vitro. The results show that in vivo, <em>Persicaria capitata </em>significantly reduced the formation rate of oxalate stones in rats, decreased the levels of urinary oxalate, sodium, potassium, calcium, and magnesium, while increasing urine pH, urinary citrate levels, and urine excretion. Moreover, <em>Persicaria capitata </em>significantly lowered serum creatinine levels in oxalate stone model rats and mitigated kidney damage. In vitro, treatment with <em>Persicaria capitata </em>extract effectively alleviated oxalate-induced oxidative stress in HK-2 cells, reducing the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing ATP levels and inhibiting oxalate-induced apoptosis. LC-MS analysis of <em>Persicaria capitata </em>components, in combination with transcriptomics, network pharmacology, and metabolomics sequencing, indicated that Myricetin might be one of its potential bioactive compounds. Both <em>Persicaria capitata </em>extract and its active compound, Myricetin, significantly reversed the oxalate-induced decrease in PI3K and ERK levels and inhibited the overexpression of oxidative stress-related proteins. Further analysis using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) experiments revealed that Myricetin exhibits strong binding affinity to PIK3CA. Moreover, PI3K inhibitors reversed the protective effects of <em>Persicaria capitata </em>and Myricetin on oxalate-induced cell injury models. <em>Persicaria capitata </em>exerts its anti-urolithiasis effects by alleviating oxidative stress through a multi-component, multi-target synergistic mechanism. Additionally, Myricetin, one of the bioactive components of <em>Persicaria capitata</em>, directly binds to PIK3CA, promoting ERK expression, upregulating NRF2 levels, and subsequently reducing oxidative stress, thereby inhibiting oxalate stone formation and alleviating kidney injury.