Chronic kidney disease (CKD) is one of the most frequent long-term disorders globally, with increasing morbidity and mortality rates in recent years [1]. The pathogenesis of CKD in adults is characterized by a glomerular filtration rate (GFR) >60 mL/min/1.73 m2 or ≥30 mg/g of urinary albumin excretion, which persists for more than 12 weeks. Current statistics reveal the global burden of disease (GBD) of CKD to be a whopping ∼850 million affected individuals, and reflect the ever-increasing CKD-associated mortalities [2]. Kidney fibrosis, primarily characterized by the excessive accumulation of pro-fibrotic markers like collagen, elastin, and fibronectin in the kidneys, leading to structural impairment, reduced blood passage to the kidneys, glomerulosclerosis, tubulointerstitial fibrosis, arteriosclerosis, and ultimately, renal failure [3]. This progression involves complex pathophysiological mechanisms, including systemic hypertension, activation of various growth factors, chemokines, and cytokines, particularly the renin-angiotensin-aldosterone system (RAAS), dyslipidemia, podocyte loss, and glycosuria. With the rising global prevalence of CKD, kidney transplantation, kidney replacement therapy (KRT), and dialysis remain the principal remedies for diseased patients. Consequently, there is an urgent need for solutions aimed at mitigating interstitial fibrosis.

Key molecular drivers of kidney fibrosis include transforming growth factor-β (TGF-β), which activates the suppressor of mother against decapentaplegic 2/3 (Smad2/3) signaling pathway, angiotensin II through AT1 receptor (AT1R) activation, connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1), and nuclear factor κ-light-chain enhancer of activated B cells (NF-κB), among others [4]. Current therapeutic interventions for CKD merely delay disease progression without effectively halting or reversing fibrosis. Research has revealed that, as a part of the TGF-β superfamily, bone morphogenetic protein (BMP) exhibits an anti-fibrotic action via the BMP/Smad1/5/8(9) signaling axis in CKD [5]. Moreover, Smad4, a bridge protein that shuttles between TGF-β/Smad2/3 and BMP/Smad1/5/9, is upregulated in CKD conditions [6]. Therefore, interventions that upregulate the BMP/Smad signaling pathway, while disrupting Smad4 protein, can serve as an effective strategy to counter the fibrotic effects of UUO.

Natural products and plant-based compounds represent a promising frontier in CKD therapeutics, offering multi-target therapeutic effects with potentially fewer adverse effects compared to synthetic drugs. In particular, CKD is alleviated with a variety of phyto-compounds, such as Isoliquiritigenin from Glycyrrhiza uralensis, which inhibit the Mincle/Syk/NF-κB pathway and reduce renal inflammation. Other notable compounds include Salidroside from Rhodiola rosea, which inhibits TLR4/MAPK/NF-κB signaling, and Emodin, which promotes autophagy and inhibits epithelial-to-mesenchymal transition (EMT) [7]. Simultaneously, for effective CKD treatments, newer technologies are being developed to accurately predict the efficacy of novel compounds. One such approach is the advent of network pharmacology, which illustrates the single-drug, multiple-target concept by identifying the compounds’ bioactivity and their synergistic effects on CKD-related molecular networks [8]. Different natural compounds, particularly those derived from traditional chinese medicine (TCM), have been investigated in the context of CKD pathophysiology, identified through network pharmacology, and subsequently validated experimentally. Notable examples include Gramine, Guben Xiezhuo decoction, and Formonentin, among others [[9], [10], [11]].

Guaiacol, a lignin compound with both methoxy and phenolic groups, is commonly found in the phenolic portion of dried roots of Angelica sinensis (Oliv.) Diels (Ginseng). Traditionally referred to as Dang Gui, Ginseng has been considered one of the most important Chinese medicines, regulating blood flow, providing pain relief, and possessing antioxidant and anti-inflammatory properties [12]. Moreover, guaiacol has been reported to provide prevention against pyresis, adult polyglucosan body disease, gastro-sparing effects, and osteoclastogenesis, among others, while its derivatives have also shown promising effects against renal fibrosis [[13], [14], [15], [16], [17]]. Thus, owing to its diverse pharmacological effects, guaiacol can benefit CKD prevention and management.

The current research systematically assessed the antifibrotic activity of guaiacol in CKD. Utilizing a computational pharmacology approach, we recognized CKD-associated targets of guaiacol and validated their interactions through molecular docking. Subsequent experimental validation in a unilateral ureteral obstruction (UUO)-induced rat model, as well as recombinant human transforming growth factor-beta 1 (rh-TGF-β1)-exposed normal rat kidney epithelial cells (NRK-52E), confirmed that guaiacol significantly attenuated inflammation, interstitial fibrosis, and extracellular matrix (ECM) deposition, while downregulating renal injury biomarkers. Mechanistically, guaiacol exerted its protective effect by upregulating the BMP/Smad1/5/9 signaling axis and reducing subsequent inflammation and oxidative stress. Taken together, this integrative computational and experimental investigation demonstrates the therapeutic promise of guaiacol and provides mechanistic insights into its potential role as a novel intervention for kidney fibrosis.