The primary kind of early malevolent bone tumour is osteosarcoma, accounting for roughly 20% of all initial sarcomas in bone and mostly occurring in children and adolescents [1]. Notably, osteosarcoma is a highly aggressive bone tumour that can spread to the lung metastasis [2]. Since the 1980s, osteosarcoma patients’ lifespan has significantly increased due to the use of aggressive multi-target chemotherapy treatment combined with upgraded surgeries [3,4]. Chemotherapy medications can provide sunshine to the patients whilst also simultaneously causing harm to the body through adverse effects [5]. However, notwithstanding breakthroughs in operation and multi-agent treatment, the life expectancy of localised osteosarcoma has remained stagnant over the last decades [6]. Furthermore, the life expectancy of osteosarcoma with metastasis condition is still abysmal, with a low chance of survival of 10–20 % [7]. Considering the prevailing status of the osteosarcoma life expectancy, the poor prognosis and the undesirable side effects of conventional drugs, the finding of innovative therapeutic agents for osteosarcoma treatment is urgently needed [8].

In the realm of osteosarcoma treatment, immunotherapy has emerged as a promising frontier [9]. Clinical trials investigating immune checkpoint inhibitors, notably nivolumab, aim to harness the body's immune response to target and eliminate cancer cells, potentially offering new avenues for treatment [10]. Precision medicine, a groundbreaking approach, is gaining traction in osteosarcoma research. This strategy involves tailoring treatment based on the individual characteristics of a patient's tumor [11]. Furthermore, adjuvant therapies have captured attention, particularly in mitigating the risk of recurrence [12]. Simultaneously, researchers are delving into targeted therapies that concentrate on specific molecular pathways implicated in osteosarcoma [13]. Tyrosine kinase inhibitors like sorafenib and mTOR inhibitors such as everolimus have been subjects of study, with the goal of identifying their potential benefits in addressing the intricacies of osteosarcoma at the molecular level [14]. Exploring combination therapies represents another avenue in osteosarcoma research [null]. These multifaceted approaches underscore the dynamic landscape of current research endeavors in the quest for more effective and tailored treatments for osteosarcoma.

Current findings has focused on looking for novel anti-cancer medications as well as re-evaluating existing drugs used to treat other disorders to determine their potential anti-tumor properties [15]. Novel medicinal chemical discovery and approval is a time-consuming and labor-intensive procedure [16]. Drug repositioning, has shown to be a successful and creative strategy which investigates possible new applications for existing compounds [17]. In this background, prazosin, a sympathomimetic agent used to treat hypertension and traumatic stress disorder, has been demonstrated to have antitumor activity against osteosarcoma [18].

One important modulator of biological functions is PI3K/Akt/mTOR signalling pathway that promotes to carcinogenesis, multiplication, invasion, cell cycle regulation, and apoptosis regulation, has been reported to become frequently hyperactivated in osteosarcoma [19]. It is well acknowledged as the basic intracellular signalling process implemented in both normal cellular metabolism and cancer pathogenesis [20]. Therefore, blocking this signalling pathway might prevent the cancer start and progression of osteosarcoma [21]. In precisely, recent data suggests that several anti-tumor drugs, such as rhaponticin [22], Eldecalcitol [23], phellamurin [null], honokiol [24], ferulic acid [25], lupeol [26], caffeoyl tyrosine [27] Cucurbitacin E [25], and andrographolide, disrupt the PI3K/Akt/mTOR pathway, thereby inhibiting osteosarcoma cell proliferation and survival.

This groundbreaking study marks the first study of mefenamic acid's remarkable antitumor capabilities in the context of osteosarcoma. Leveraging human osteosarcoma MG-63 cells and a xenograft mice model, we unveil the potent anticancer effects of mefenamic acid. Widely acknowledged for its efficacy in alleviating pain associated with conditions such as toothaches and menstrual cramps [28], mefenamic acid has previously demonstrated its anticancer potential against colon cancer [29], prostate cancer (Soriano-Hernández et al., 2012), and liver cancer (Woo et al., 2004). Thus, our research endeavors to unravel the untapped anti-tumor potential of mefenamic acid and delve into the underlying mechanisms that govern its impact on osteosarcoma cells, shedding light on a promising avenue for cancer therapy. The current study aligns with existing literature on mefenamic acid and its antitumor properties by confirming and extending the understanding of its potential in osteosarcoma treatment [30]. While prior research has hinted at the anticancer effects of mefenamic acid, our study contributes by providing comprehensive insights into its multifaceted impact on MG-63 osteosarcoma cells. The study corroborates earlier findings of mefenamic acid's anti-proliferative effects, yet it goes further by elucidating its role in inducing cytotoxicity, inhibiting migration and invasion, and triggering apoptosis in a dose-dependent manner. Moreover, the exploration of mefenamic acid's influence on the PI3K/Akt/mTOR pathway adds a novel dimension, offering a potential mechanistic explanation for its observed antitumor effects. By substantiating and expanding upon existing knowledge, our study contributes to a more thorough understanding of mefenamic acid's potential as a therapeutic agent against osteosarcoma.