Liver cancer, particularly hepatocellular carcinoma (HCC), which accounts for 75 %–85 % of all liver cancer cases, is the third leading cause of cancer death globally as of 2020 [1]. Unfortunately, most HCC patients present symptoms at advanced stages, rendering surgical resection largely ineffective [2]. Additionally, advanced HCC frequently shows resistance when treated with targeted therapies such as sorafenib, lenvatinib, regorafenib, cabozantinib, as well as immune checkpoint inhibitors like nivolumab and atezolizumab [3]. This resistance highlights the urgent need for effective new treatment strategies. Considering the importance of drug safety, the exploration of anti-tumor compounds derived from natural sources has become a key focus in cancer drug research [4]. Further investigation into the mechanisms by which natural substances induce cell death in HCC cells could significantly advance the development of effective treatments, potentially positioning these agents as future therapeutics for HCC.

Demethoxycurcumin (DMC), a natural compound extracted from turmeric, has shown promising antineoplastic activity across various cancer types [5]. Recent studies have indicated that DMC can inhibit cervical cancer cell growth by modulating PPARγ-related pathway [6]. Kao et al. discovered that DMC can suppress PI3K/Akt axis to initiate apoptosis in HER2 overexpressing bladder cancer cells [7]. In addition, modulation of the TP and ERCC-1 pathways by DMC can enhance the sensitivity of non-small cell lung cancer cells to cisplatin [8]. Moreover, in prostate cancer, inhibition of HSP70 and EGFR by DMC through AMPK signaling demonstrates its anticancer capabilities [9]. Furthermore, DMC has been reported to repress lipogenic enzymes and oncogenic signaling pathways by facilitating AMPK signal in triple-negative breast cancer cells to exert its anti-cancer effects [10]. Additionally, DMC can also induce apoptosis and impede the Akt/NF-kB survival pathway, contributing to the suppression of glioblastoma (GBM) cell progression [11]. These findings underscore potential of DMC as an effective anticancer agent. However, its efficacy against HCC remains unexplored, necessitating further investigation into the specific role and mechanism of DMC in HCC treatment.

Recently, altered metabolism has emerged as a critical hallmark of cancer cells, enabling them to meet their biosynthetic and energy needs for survival and growth [12]. Therefore, targeting tumor metabolism precisely may offer a promising strategy to hinder cancer progression and potentially eradicate cancer cells. Historically, Otto Warburg concluded that cancer cells predominantly rely on aerobic glycolysis while suppressing mitochondrial function [13]. This metabolic preference has been shown to contribute to HCC progression in various studies [14]. Nonetheless, several prior investigations have indicated that most cancer cells maintain active mitochondria and utilize oxidative phosphorylation (OXPHOS) to meet a part of ATP requirement [15,16]. Additionally, Birsoy K et al. have identified that OXPHOS is essential for optimal growth and survival of cancer cells under glucose-depleted conditions, which are common in tumor microenvironment [17]. Moreover, mitochondrial metabolism is crucial for synthesizing anabolic precursors that support rapid cancer cell growth [18]. Interestingly, a recent study reported that FUNDC2 can effectively inhibit MFN-1-induced mitochondrial elongation, promoting mitochondrial OXPHOS and thus facilitating liver tumorigenesis [19]. These findings underscore the indispensable roles of both aerobic glycolysis and mitochondrial metabolism in the development of HCC. However, the relationship among DMC, HCC, and bioenergetics metabolism remains unreported.

Interestingly, recent study has demonstrated the curcumin derivative can regulate bioenergtic metabolism to participate in tumor progression. Wang et al. found that curcumin derivative WZ35 can mediate metabolic reprogramming dominated through impaired glycolysis and oxidative phosphorylation to inhibit the proliferation activity of liver cancer cells [20]. These findings indicated that curcumin derivative may obtain the ability to regulate bioenergetic metabolism. Thus, in this study we aimed to determine whether these two vital bioenergetic pathways can also be targeted by DMC and to elucidate the underlying molecular mechanisms.