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Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.

Epithelial‐to‐mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator‐activated receptor (PPAR)‐γ, a ligand‐activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR‐γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR‐γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR‐γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2‐furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR‐γ partial activation. QDs‐treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI‐H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E‐box binding homeobox 1) and concomitant upregulation of epithelial marker (E‐cadherin).

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