Colorectal cancer (CRC) is one of the most prevalent cancers worldwide [1] and is the second most common cause of cancer death [2]. Recent statistics indicate that in 2022, there were approximately 4.82 million new cancer cases and 3.21 million cancer deaths in China and 2.37 million new cases and 640,000 deaths in the USA [3,4]. A recent modeling study estimated that there will be between 4000 and 7000 excess deaths from CRC by 2040 [2]. The increasing incidence of CRC, especially among younger populations, poses a significant public health challenge and economic burden [5,6]. Although surgery combined with chemotherapy remains a cornerstone of CRC treatment, the prognosis for patients is often poor, with a recurrence rate exceeding 30 % after radical surgery [7]. Therefore, identifying novel CRC-associated genes is crucial for developing effective therapeutic strategies.

There is a strong correlation between the oxidative state and oncogenesis in CRC. Enzymatic and nonenzymatic antioxidants are able to regulate redox homeostasis by eliminating reactive oxygen species (ROS) to prevent oxidative damage. For instance, superoxide anion (O2−) is converted into H2O2 by superoxide dismutase (SOD), and H2O2 is decomposed into water and oxygen by catalase (CAT) [8]. Oxidative stress occurs when the accumulation of ROS, including O2−, hydroxyl radical (•OH), and non-radical molecules such as hydrogen peroxide (H2O2) and singlet oxygen (1O2) [9,10], exceeds the neutralizing capacity of intrinsic antioxidants and antioxidant defenses, which in turn affects CRC oncogenesis [11]. However, the precise mechanistic link between oxidative stress and CRC oncogenesis remains incompletely understood.

Methionine sulfoxide reductase B1 (MsrB1) is a member of the selenoprotein family, characterized by a catalytic site containing selenocysteine (Sec). The inclusion of Sec enhances the antioxidative capacity of selenoproteins beyond that of typical cysteine-containing proteins [12,13]. Initially recognized as an enzymatic antioxidant involved in the oxidative damage repair of biomolecules [14], MsrB1 specifically reduces free or protein-bound R-methionine sulfoxide (R-MetO) back to methionine (Met) [15]. Given its antioxidative function, studies on MsrB1 have primarily focused on oxidative damage-related diseases such as diabetes and its complications, cardiovascular diseases, and neurodegenerative disorders [16]. In 2021, our research revealed that MsrB1 facilitates the proliferation and invasion of CRC cells via the GSK-3β/β-catenin signaling axis [15]. Subsequently, a pan-cancer bioinformatics analysis identified MsrB1 as a promising predictive biomarker and therapeutic target [17]. Notably, we were the pioneers in discovering and reporting the role of MsrB1 in CRC and have continued to conduct in-depth research [15,17]. It is worth mentioning that in the field of cancer research, only a few studies related to MsrB1, besides our work, have been reported [18,19].

In this study, we investigated and validated the molecular mechanisms by which MsrB1 contributes to CRC progression. We identified Krüppel-like factor 5 (KLF5), a member of the Krüppel-like factor (KLF) family [20], as a novel transcriptional regulator of MsrB1. Furthermore, we discovered that MsrB1 interacts with β-catenin, a key component of the canonical Wnt pathway, to activate Wnt signaling and promote oncogenesis. This finding aligns with our previous research [15], reinforcing the critical role of the Wnt pathway in MsrB1-mediated tumor development. A significant downstream effect of the Wnt pathway includes the inhibition of ferroptosis, a form of iron-dependent cell death. We demonstrate that the interaction between MsrB1 and β-catenin leads to the upregulation of GPX4 transcription, a critical ferroptosis-related biomarker, which inhibits ferroptosis and promotes CRC oncogenesis. Our findings suggest that MsrB1 holds significant potential as a therapeutic target for CRC, offering a new strategy for clinical treatment.