Since 1990, the global burden of chronic kidney disease (CKD) has escalated markedly, with prevalence increasing by 29.3%, and mortality rising by 41.5%, constituting a major public health challenge (GBD Chronic Kidney Disease, 2020). However, early-to-moderate stage CKD is highly preventable and potentially reversible (Shlipak et al., 2021). Regrettably, the clinically silent nature of incipient CKD precludes timely intervention, frequently permitting inexorable progression to end-stage renal disease (ESRD). This trajectory is evidenced by a doubling of ESRD prevalence over the past 2 decades (Kuehn, 2022). Renal fibrosis (RF) represents the terminal pathological convergence in CKD progression, morphologically characterized by glomerulosclerosis, tubular atrophy, vascular rarefaction, and interstitial fibrosis, culminating in excessive extracellular matrix (ECM) deposition and scar formation (Huang et al., 2023; Li L. et al., 2022). Conventionally, RF pathogenesis was attributed to aberrant cellular phenotypic plasticity, encompassing mesenchymal transformation of renal epithelial and endothelial cells (EMT/EndMT) and pathological activation of matrix-producing myofibroblasts (Yamashita and Kramann, 2024). However, contemporary research has elucidated previously unrecognized regulatory axes governing fibrogenic commitment, including non-coding RNA networks (Van der Hauwaert et al., 2019), epigenetic modifications (Li X. et al., 2022), metabolic reprogramming (Zhu et al., 2021), and extracellular vesicles-mediated signaling (Kosanović et al., 2021). These mechanisms present promising direction for modulating—and potentially reversing—established fibrosis. Despite these mechanistic advances, no therapeutics directly and selectively targeting RF pathogenesis are clinically available (Huang et al., 2024). Consequently, current clinical practice relies on agents developed for broader CKD management—angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 inhibitors (SGLT2i) —to indirectly attenuate fibrotic progression (Wang and Zhang, 2024). Nevertheless, their efficacy remains suboptimal and variable, while safety profiles are constrained by underlying etiological heterogeneity, disease stage disparities, and diverse environmental determinants (Reiss et al., 2024).

Consequently, our focus centers on the G protein-coupled receptors (GPCRs) superfamily, Representing the largest cohort of human membrane proteins and historically constituting the most therapeutically exploited target class, GPCRs hold profound significance (Zhang et al., 2024). Within nephrology, GPCR-directed pharmacotherapies have established pivotal clinical utility (Lv et al., 2024; Tang et al., 2025). The most substantiated classes encompass AT1R antagonists (Rianto et al., 2021), GLP-1R agonists (Rossing et al., 2023), ETR antagonists (Martínez-Díaz et al., 2023) and dual angiotensin/endothelin receptor antagonists (Kohan et al., 2024), collectively demonstrating immense promise for innovative renal disease drug development (Table 1). Critically, GPCR-targeted agents constitute the predominant share of receptor-focused therapeutic candidates in current clinical trials for RF (Abbad et al., 2025). Moreover, we emphasize that GPCR signal transduction and functionality are intimately implicated in the initiation and modulation of RF (Tang et al., 2025). Consequently, despite the formidable global challenge of developing effective clinical interventions for RF, the therapeutic promise of targeting GPCRs—leveraging their well-defined pathophysiological roles and notable inherent druggability—is increasingly commanding significant scientific and clinical attention.

GPCRs belong to the family of seven-transmembrane proteins. The human genome encodes approximately 800 GPCRs that orchestrate diverse physiological and pathophysiological processes across multiple organ systems (Congreve et al., 2020). The transmembrane helix structure comprises the extracellular N-terminus, three extracellular loops, an intracellular C-terminus, and three intracellular loops. Heterotrimeric G proteins, consisting of α, β, and γ subunits, serve as primary signaling partners. In the basal state, Gα subunits remain guanosine diphosphate (GDP)-bound and conformationally constrained. Ligand engagement induces allosteric transitions within the receptor’s transmembrane core, catalyzing GDP-guanosine triphosphate (GTP) exchange on the Gα subunit, This nucleotide switch triggers dissociation of the GTP-bound Gα subunit from the Gβγ dimer (Ballante et al., 2021) (Figure 1). The liberated Gα-GTP complex and Gβγ heterodimer regulate distinct downstream effectors. Gα subunits are phylogenetically categorized into four classes: Gαs, Gαi/o, Gαq/11, and Gα12/13. For example, Gαs primarily activates adenylate cyclase (AC), promoting the production of cAMP. Conversely, Gαi/o inhibits AC and cAMP activity; Gαq/11 binds with phospholipase C-β (PLCβ) to promote the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which further activates downstream protein kinase C (PKC) and triggers Ca²⁺ release. The downstream signaling of Gα12/13 primarily involves Rho GTPase, with a more complex and diverse regulatory pattern (Rasheed et al., 2022; Jiang et al., 2022). The Gβγ complex independently regulates ion channels, kinases, and secondary messenger systems (Senarath et al., 2018). Signal termination is mediated by regulator of G protein signaling (RGS) domains, which accelerate GTP hydrolysis via intrinsic GTPase-activating protein (GAP) activity. Gα-GDP subsequently reassociates with Gβγ, reconstituting the inactive heterotrimer and completing the catalytic cycle (Masuho et al., 2023). Additionally, GPCR activation is partially independent of G proteins. For example, phosphorylated GPCRs recruit β-arrestins, which prevent G protein signaling and promote receptor internalization, initiating new signaling pathways (Asher et al., 2022). Furthermore, most adhesion GPCRs (aGPCRs) contain a special domain with a hydrolysis site. Their self-proteolysis leads to aGPCR autoactivation, causing the separation of Gα from Gβγ and initiating downstream signaling (Zhu X. et al., 2022).

Concurrently, emerging research has revealed intimate connections between RF pathogenesis and GPCR signaling cascades. Therapeutic targeting of the cAMP/PKA pathway (Stokman et al., 2021), Gβγ-GRK2 interface (Rudomanova and Blaxall, 2017), and β-arrestin-dependent signaling (Gu et al., 2015) has emerged as a validated strategy for antagonizing RF progression. Furthermore, the intricate crosstalk among non-coding RNAs (ncRNAs), epigenetic modifications, and GPCR regulation constitutes a pivotal investigative frontier (Zhao et al., 2014; Alghamdi et al., 2018; Liu et al., 2019). Supporting this paradigm, transcriptomic profiling of proximal tubule-mediated RF identifies 143 differentially expressed lncRNAs and 91 dysregulated GPCRs (Wu H. et al., 2020), whereas CaSR signaling—primarily orchestrating Ca²⁺ and water transport—demonstrates extensive miRNA interactions (Ranieri, 2019). Critically, bidirectional regulatory crosstalk exists between GPCR signaling cascades and ncRNAs networks. GLP-1R not only governs the circ8411/miR-23a-5p axis to mitigate lipid toxicity and endothelial pyroptosis (Wu W. et al., 2024) but is reciprocally modulated by extracellular vesicle-encapsulated miR-192 to exert renoprotection (Jia et al., 2018). Moreover, In butyrate-mediated protection against diabetic nephropathy (DN), GPR41, GPR43, and GPR109A engage in crosstalk networks involving histone deacetylase (HDAC) inhibition, histone butyrylation, and miRNA repertoire alterations, collectively modulating DN-associated inflammatory and fibrotic pathologies (Cheng et al., 2022). Notably, GPR109a activation rectifies promoter region acetylation and methylation patterns, preserving glomerular basement membrane (GBM) integrity (Felizardo et al., 2019). These findings establish ncRNAs and epigenetic machinery as critical upstream regulators of GPCR functionality, thereby revealing their therapeutic potential as precision targets for renal fibrosis intervention.

Within the kidneys, GPCRs exhibit ubiquitous expression and critically orchestrate essential physiological processes including renal development, fluid-electrolyte homeostasis, and blood pressure regulation (Table 2). Spatiotemporal mapping of GPCR distribution across nephron segments reveals prominent enrichment of aGPCRs, adrenergic receptors (ARs), and lysophosphatidic acid receptors (LPARs) along renal tubules (Poll et al., 2021). In alignment with prior evidence of olfactory receptors (ORs) participating in renal physiology (Kalbe et al., 2016), this profiling further identifies substantial enrichment of ORs along the nephron (Poll et al., 2021). In the renal vasculature and glomeruli, receptors including GPR91, GPR43, and apelin receptor (APJ) are functionally co-expressed and collectively participate in renal physiological regulation (Rajkumar and Pluznick, 2017). Moreover, Transcriptomic profiling identifies 56 GPCRs dysregulated in activated renal fibroblasts, underscoring their pathogenic involvement in fibrogenesis (Kaur et al., 2023). Developmental regulation is exemplified by GPR126, which exhibits progressive upregulation in ureteric buds and renal epithelia during murine nephrogenesis. Its persistent expression in mature tubular epithelium and collecting ducts implicates roles in progenitor cell differentiation and renal morphogenesis (Cazorla-Vázquez and Engel, 2018; Cazorla-Vázquez et al., 2023). Apically expressed GPR37L1 in renal tubular epithelial cells enhances Na⁺/H⁺ exchanger isoform 3 (NHE3) activity, thereby promoting natriuresis and diuresis. This regulation potentially involves cAMP dynamics and PI3K/AKT/mTOR signaling (Zheng et al., 2019; Armando et al., 2022). Notably, GPCR-NHE3 crosstalk establishes a novel paradigm for fluid-electrolyte homeostasis via coordinated intra- and extracellular pH/ion balance. For example, OGR1 inhibits NHE3 activity to mediate renal calcium excretion (Imenez Silva et al., 2020), whereas GPRC5C elevates its activity to regulate systemic pH (Rajkumar et al., 2018). Furthermore, renal perfusion-sodium excretion equilibrium crucially maintains blood pressure stability, with key contributions from Dopamine receptors (DRs) (Yang J. et al., 2021), prostaglandin receptors (EPRs) (Wang et al., 2022), and Angiotensin Receptors (ATRs) (Colafella et al., 2016).

Meanwhile, the GPCR superfamily orchestrates pivotal pathological processes in renal diseases, including inflammatory cascades, immune dysregulation, fluid-electrolyte imbalances, and RF (Lv et al., 2024). Inflammation serves as the primary instigator of renal injury, wherein complement C5aR activation drives pathogenesis in inflammatory nephropathies such as lupus nephritis (Ye et al., 2024), ANCA-associated vasculitis (Xiao et al., 2014), and acute pyelonephritis (Li et al., 2017). Autoimmune mechanisms further characterize renal pathology, with chemokine receptors (CCRs) orchestrating leukocyte trafficking and tissue infiltration (Hamdan and Robinson, 2021). Notably, CXCR3-dependent immune cell crosstalk represents an emerging therapeutic target (Yoshikawa et al., 2023). In contrast to normal homeostatic functions, AT1R (Dalman and Coleman, 2023), V2R (Bankir et al., 2010), and ETRs (Hunter et al., 2017) promotes sodium-water retention and hypertensive nephropathy (HN). RF, a hallmark pathological endpoint of progressive CKD, is orchestrated by GPCRs at multiple regulatory tiers. For instance, Prostaglandin E2 (EP2) engages four distinct EPR subtypes to stimulate diverse intracellular signaling cascades (Mutsaers and Nørregaard, 2022). LPA activates six GPCR subtypes that drive immune cell recruitment and sustain profibrotic mediator production (Park and Miller, 2017). Emerging evidence further elucidates the contributions of ORs (Motahharynia et al., 2022), GPCR-Gβγ complexes (Kamal et al., 2017), and GPCR-β-arrestin-biased pathways (Gu et al., 2015) in RF pathogenesis, collectively unveiling viable therapeutic strategies to reverse fibrosis. In summary, GPCRs exhibit profound dualistic involvement in renal physiology and pathobiology, positioning them as high-priority therapeutic targets for innovative renal disease interventions.

Notwithstanding the preeminent status of GPCRs as the most therapeutically exploited target class, their translational deployment against fibrotic disorders remains incipient (Tang et al., 2025; Rieder et al., 2025). This therapeutic inertia predominantly arises from the intricately orchestrated, multifactorial pathoetiology of organ fibrosis, characterized by dynamic oscillations between inflammatory and profibrotic signaling cascades (Abbad et al., 2025). Mononodal pharmacotherapeutic interventions targeting singular nodal points are frequently subverted by compensatory pathway rewiring—a phenomenon starkly evidenced by terminated clinical trials targeting canonical profibrotic networks (e.g., TGF-β, PI3K/mTOR, JAK/STAT) (Di et al., 2025; Zhao et al., 2022). Concomitantly, extant in vitro and in vivo fibrosis models exhibit limited recapitulation of the human pathophysiological niche, thereby compromising translational fidelity (Addario et al., 2025). Furthermore, the pathologically remodeled ECM in RF imposes steric hindrance that severely restricts lesional drug bioavailability (Xu et al., 2021). Therefore, overcoming the bottlenecks in targeted GPCR intervention for organ fibrosis is of crucial importance.

Despite these challenges, combining computational and experimental tools is driving significant progress. Innovations in 3D microphysiological systems—encompassing organ-on-chip platforms with multicellular co-cultures, vascularized bioprinted constructs, and patient-derived organoids—are progressively standardizing human-relevant fibrotic pathomimetics (Addario et al., 2025; Sacchi et al., 2020; Miyoshi et al., 2020). Parallel breakthroughs in nanotherapeutic delivery—including lipid-encapsulated GPCR ligands, renal-compartment-specific targeting moieties, and pathology-responsive nanovehicles—are circumventing biodistribution barriers (Oroojalian et al., 2020). In GPCR drug discovery, AI-driven compound design and biased ligand development are reaching maturity (Zhang et al., 2024; Yang D. et al., 2021), GPCR-targeted candidates now make up over 60% of receptor-focused clinical pipelines for fibrosis. Key examples include clinical trials targeting S1PR (e.g., Fingolimod), CCR2 (e.g., DMX-200), and GLP-1R (e.g., Exenatide) epitomize this mechanistic momentum (Abbad et al., 2025). Collectively, the precision targeting of GPCR signaling nodes harbors exceptional potential for intercepting the fibrotic cascade at its evolutionary nexus.

Given the persistent high disease burden and suboptimal therapeutic outcomes in RF, convergent preclinical and clinical evidence has validated the therapeutic tractability of GPCRs. This review delineates the pathophysiological primacy of key GPCR families—notably endothelin, angiotensin, chemokine, and adenosine receptors—in orchestrating RF progression through multimodal regulation spanning inflammatory/fibrogenic cascade initiation, maladaptive cellular phenotypic transitions, metabolomic reprogramming, and mechanotransductive injury responses. Collectively, GPCRs emerge as supramolecular signaling hubs whose precision modulation holds exceptional promise for next-generation anti-fibrotic therapeutics.