GPCRs, a family of transmembrane proteins representing 3% of the human genome, play a pivotal role in cellular signaling at both extracellular and intracellular levels, making them potential targets for therapeutic intervention [1]. Among these receptors, GPR35, a transmembrane receptor with three variants [2], has gained considerable attention due to its unique features as addressed. Variants 2 and 3 express longer isoforms (GPR35b), whereas variant 1 expresses the short isoform (GPR35a) [3]. Its ubiquity in various tissues, including the immune cells, central nervous system, cardiovascular system, gastrointestinal tract, lung, bone, and liver, makes it a multifaceted player compared to other GPCRs in cellular communication. The dynamic interplay of ligand interactions of GPR35 or its spontaneous autoactivation leads to the transduction of various signaling pathways discussed below extensively, including p-Akt, p-Erk, RhoA, p-Src, NF-Kb, and calcium-induced signaling [4]. Additionally, evidence highlights that GPR35 expression in tissues is often associated with poor prognosis and survival at the patient level, thus making it a pharmacological target [5], [6]. To impede the signal transduction pathway induced by endogenous ligands or spontaneous autoactivation of GPR35-mediated signaling, the antagonist of GPR35 is frequently investigated. Currently, three antagonists targeting GPR35 have been identified, with CID-2286812 (ML145) exhibiting exceptionally high affinity and selectivity compared to GPR55 [7]. GPR35 shares similarities with other GPCRs at the structural level [8]; however, the pervasive expression, intricate signal activation, mechanism of ligand-receptor relationship, and opportunities for developing novel agents have garnered attention from researchers into the pathophysiology and pharmacology of GPR35. Thus, GPR35 is rationalized as one of the unique receptors in relation to other known GPCRs. In addition to these fascinating features, GPR35 remains obscure and controversial, particularly in terms of its ligands. Based on this context, several putative candidates have been proposed, including kynurenic acid (KYNA), lysophosphatidic acid (LPA), and chemokine CXCL17. Although studies refuted the fact of CXCL17 activating GPR35 thus challenging our understanding towards the potential ligand candidate [4], [9]. However, the other known GPCRs do not show such controversial status concerning their ligands. For instance, the CXCR4-CXCL12 interactome was reported in various tumor metastasis and growth with no overlap based on ligand interaction [10]. A study established LPA and L-KYNA as the ligand of distinct receptors, including GPR35 [11], [12]. Additionally, GPR35 antagonists offer species selectivity, underlining the challenges for targeting GPR35 [13]. Therefore, this makes GPR35 a unique member of GPCR, which requires the utmost attention from researchers to answer the controversial stories of ligand biases and truly evaluate the therapeutic value of GPR35.

This review comprehensively covers GPR35’s structure, expression patterns, potential endogenous ligands, and their roles in various pathologies. Additionally, we have provided insights into the antagonist of GPR35, shedding light on the challenges faced in developing effective compounds. The pathological role of GPR35, along with its endogenous ligands in different malignancies, associated signaling pathways, and the impact on the immune system, are discussed. Overall, the review sheds light on the intricate and significant role of GPR35, emphasizing its potential therapeutics value.