KLF16 transcriptionally activates HSPB1 to participate in the sorafenib resistance of hepatocellular carcinoma by driving ferroptosis resistance.

BACKGROUND

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The primary therapeutic drug for advanced HCC is sorafenib (Sora), but drug resistance severely affects its efficacy. The present study aimed to investigate the role of the transcription factor KLF16 in Sora resistance in HCC.

METHODS

An HCC tumor-bearing model was constructed by subcutaneously injecting HepG2 cells into the right abdomen of nude mice. CCK-8, colony formation, and Transwell assays were used to evaluate cell viability. RTqPCR and Western blot analyses were employed to detect gene and protein expression. Kits were used to measure ferroptosis-related indicators, including Fe²⁺, MDA, ROS, and GSH levels. ChIPqPCR was performed to assess the interaction between KLF16 and HSPB1.

RESULTS

KLF16 expression is significantly upregulated in HCC. KLF16 knockdown inhibits HCC cell viability, colony formation, and invasion ability but enhances the inhibitory effect of Sora on the growth of xenograft tumors in nude mice. KLF16 knockdown promotes the sensitivity of HCC cells to Sora, whereas KLF16 overexpression has the opposite effect. KLF16 enhances HCC resistance to Sora by inhibiting ferroptosis. Moreover, HSPB1 is also upregulated in HCC, and KLF16 acts as a transcriptional regulator of HSPB1 to promote its expression. HSPB1 overexpression promotes HCC cell proliferation and invasion but inhibits ferroptosis.

CONCLUSION

KLF16, as a transcription factor, upregulates HSPB1 expression and promotes HCC resistance to Sora by inhibiting ferroptosis. KLF16 may be a potential therapeutic target to overcome Sora resistance in HCC.