<p>Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer that poses a serious threat to women’s health. The aldo-keto reductase type 1&#xa0;C (AKR1C) family serves as a crucial ferroptosis defense system, catalyzing the conversion of aldehydes and ketones into their corresponding alcohols. SRY-Box4 (SOX4), a transcription factor of the SOX (sry-related HMG-box) family, is important in regulating tumor progression. This study aims to investigate the mechanism through which AKR1C1 mediates the growth, invasion, and ferroptosis of triple-negative breast cancer cells. SRPX2 was highly expressed in TNBC tissues and cells and was detrimental to patient prognosis. SRPX2 knockdown inhibited TNBC cell viability, invasion, and Stemness of tumor while promoting TNBC cell apoptosis and ferroptosis. SOX4 could bind to SRPX2 and was highly expressed in TNBC tissues and cells, down-regulation of SOX4 could inhibit the expression of SRPX2. Silencing SRPX2 inhibited the expression of AKR1C1. Up-regulating AKR1C1 reversed the inhibitory effect of SRPX2 knockdown on cell viability, invasion, and sphere formation abilities, and also reversed the promotive effect on apoptosis in TNBC cells. In vivo, SRPX2 knockdown suppressed tumor growth and expression of Ki67 and AKR1C1 via down-regulated AKR1C1. SOX4 facilitates triple-negative breast cancer progression via promoting SRPX2 transcription to regulate AKR1C. This study is expected to explore potential therapeutic targets and strategies for the treatment of TNBC. </p>