As a common malignancy in the urinary system, renal cell carcinoma (RCC) originates from the renal epithelium and accounts for more than 90 % of all cases of kidney cancer, with an estimated 434, 840 diagnosed cases worldwide in 2022 [1]. Furthermore, clear cell RCC (also known as kidney renal clear cell carcinoma, KIRC) is the prevalent histological subtype of RCC, responsible for about 80 %–90 % of all cases [2]. Additionally, KIRC is a major global health issue that can lead to severe morbidity and mortality rates [3]. Clinically, early-stage KIRC has a better prognosis and can be extensively cured by surgery, while advanced KIRC has limited treatment options due to insensitivity to conventional radiotherapy and chemotherapy [[4], [5], [6]]. Due to untypical early symptoms, approximately 25 %–30 % of KIRC patients have metastasis at the time of initial diagnosis [7]. Besides, about 30 % of patients develop metastatic recurrence after nephrectomy [8]. Significant advances in various management approaches such as targeted therapies and immunotherapies have recently acquired some benefits, but patients with advanced/metastatic KIRC remain frustrated [9,10]. Therefore, elucidating the molecular mechanisms driving KIRC progression is important for exploring novel therapeutic agents or identifying relevant targets.

As an essential ancient membrane-bound organelle present in nearly all eukaryotic cells, mitochondria produce the energy required for tumor cell survival and activity via oxidative phosphorylation (OXPHOS) and mitochondrial respiratory chain [11]. In general, it provides energy to the cell primarily in the form of adenosine triphosphate (ATP) by breaking down organic molecules such as glucose and fatty acids through OXPHOS [12]. Moreover, the mitochondrial respiratory chain is responsible for the main source of intracellular ROS, which plays a vital role in maintaining redox balance and intracellular signal transduction [13]. Reportedly, enhanced intracellular oxidation and stress from mitochondrial dysfunction can disrupt endoplasmic reticulum and lysosomal activities, thereby activating autophagy and subsequently affecting cell damage and death [14,15]. Beyond that, dysfunction of mitochondria can also result in metabolite production triggering signaling cascades that affect gene expression, cell proliferation, and differentiation [16,17]. Considering that cellular metabolic reprogramming and aberrant redox status are key features of tumor transformation, targeting mitochondria might represent a crucial approach to repress tumor growth and improve their sensitivity to therapy. Notably, multiple studies have indicated that abnormal lipid accumulation, metabolic alterations, and autophagy could endow KIRC with a high-energy state and resistance to treatment [[18], [19], [20]]. Pan-RCC clustering based on RNA sequence data identified a histology-independent subgroup that is featured by augmented mitochondria-related gene signatures and diminished angiogenesis-associated gene signatures [21]. Several metabolites have been reported to be correlated with glutathione synthesis, an antioxidant buffering ROS produced by mitochondria in aggressive subclasses of KIRC [22]. Indeed, recent literature has identified the molecular characteristics and prognostic significance of the mitochondrial genes related to oxidative stress in KIRC [23]. However, the specific molecular mechanisms targeting oxidative stress-associated mitochondria in KIRC patients remain unclear.

The most predominant post-translational modification in eukaryotic cells is N6-methyadenosine (m6A), which affects mRNA degradation, stability, translation, and nuclear export [24]. As an invertible and plentiful modification of RNAs, m6A can be installed by a large methyltransferase complex (“writers”), removed by demethylases (“erasers”), containing FTO and ALKBH5, and recognized by m6A binding proteins (“readers”), such as YTHDC1/2 and YTHDF1/2/3. It has been reported that the methyltransferase complex is comprised of METTL3/14, WTAP, and zinc-finger CCCH-type containing 13 (ZC3H13). Among them, METTL3-METTL14 heterodimer has been identified as the primary catalytic subunit. Of interest, several reports have indicated that ZC3H13 can modulate the m6A modification by retaining the m6A writer complex within the nucleus [25]. In addition, ZC3H13 acted as a tumor suppressor by repressing cell proliferation and invasion in papillary thyroid carcinoma (PTC) [26] and colorectal cancer [27]. A recent study has confirmed the aberrant downregulation of ZC3H13 in KIRC [28], but its role and molecular mechanism in the tumor are far from being addressed.

Belonging to the glutathione peroxidase family, glutathione Peroxidase 4 (GPX4) has a selenocysteine at the active site catalyzing ROS detoxification in the form of reduced glutathione [29]. Convincing evidence has indicated that GPX4 is involved in the regulation of mitochondrial dysfunction in lung cancer [30]. It has been reported that overexpressing GPX4 is indicative of the progression of KIRC with a poor prognosis [31]. Apart from that, GPX4 upregulation promoted KIRC cell growth, migration, and invasion [32]. Herein, the possible m6A sites of GPX4 mRNA were found. Moreover, GPX4 was a target of ZC3H13. Hence, we aimed to investigate whether ZC3H13 affects KIRC progression by regulating GPX4.