The transcription factor TFEB is a major regulator of lysosomal biogenesis and autophagy. There is growing evidence that posttranslational modifications play a crucial role in regulating TFEB activity. Here, we show that lactate molecules can covalently modify TFEB, leading to its lactylation and stabilization. Mechanically, lactylation at K91 prevents TFEB from interacting with E3 ubiquitin ligase WWP2, thereby inhibiting TFEB ubiquitination and proteasome degradation, resulting in increased TFEB activity and autophagy flux. Using a specific antibody against lactylated K91, enhanced TFEB lactylation was observed in clinical human pancreatic cancer samples. Our results suggest that lactylation is a novel mode of TFEB regulation and that lactylation of TFEB may be associated with high levels of autophagy in rapidly proliferating cells, such as cancer cells.

Objective: To investigate the clinical value of combining systematic prostate biopsy with contrast-enhanced ultrasound (CEUS)-guided targeted biopsy in patients with serum prostate-specific antigen (PSA) levels in the gray zone. Methods: A total of 167 patients in the PSA gray zone treated at Zhejiang Provincial Hospital of Traditional Chinese Medicine from January 2022 to October 2024 were retrospectively analyzed and divided into a systematic biopsy group and a combined biopsy group. Both groups underwent transperineal biopsy under transrectal ultrasound guidance. In the combined biopsy group, CEUS was used to identify suspicious lesions for targeted biopsy, followed by reduced-core systematic biopsy in non-targeted regions; both groups received 10-core biopsies. Results: The combined targeted biopsy group showed significantly higher detection rates for prostate cancer (PCa) (57.32% vs. 30.59%; OR = 3.05, 95% Confidence interval(CI) 1.61–5.76; Absolute risk difference ( ARD ) = 26.7%) and clinically significant prostate cancer (csPCa) (46.34% vs. 12.94%; OR = 5.81, 95% CI 2.70–12.52; ARD = 33.4%) than the systematic biopsy group (all P < 0.001). The combined targeted group also yielded more positive biopsy cores (2.05 ± 2.32 vs. 0.80 ± 1.68, P < 0.001) and a higher proportion of Gleason score ≥ 7 lesions among detected PCa cases (80.85% vs. 42.31%, P < 0.001). Subgroup analyses suggested greater diagnostic benefits in patients aged > 70 years or with prostate volume ≤ 60 mL. Multivariate regression confirmed biopsy method as an independent predictor for both PCa ((Adjusted odds ratio( aOR ) = 2.619, P = 0.008) and csPCa ( aOR = 5.171, P < 0.001). Complication rates did not differ significantly between the two groups (all P > 0.05). Conclusion: CEUS-guided systematic biopsy combined with targeted biopsy significantly improves the detection rates of PCa and csPCa in patients with PSA gray zone levels, with a favorable safety profile. Subgroup analyses suggest that older patients and those with smaller prostate volumes may derive greater benefits; however, these exploratory findings warrant confirmation in future prospective studies.