Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority. Our previous research demonstrated the efficacy of artesunate (ART) in alleviating liver fibrosis by eliminating activated hepatic stellate cells (HSCs). However, the underlying mechanism remains unclear despite these findings. Notably, endocytic adaptor protein (NUMB) has significant implications for treating hepatic diseases, but current research primarily focuses on liver regeneration and hepatocellular carcinoma. The precise function of NUMB in liver fibrosis, particularly its ability to regulate HSCs, requires further investigation. This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs. We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs, exhibiting a negative correlation with the progression of liver fibrosis. Additionally, ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor (P53) axis. We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate. This research examines the specific target of ART in eliminating activated HSCs, providing both theoretical and experimental evidence for the treatment of liver fibrosis.
Hepatic Stellate Cells/cytology* ; Liver Cirrhosis/genetics* ; Artesunate/pharmacology* ; Cellular Senescence/drug effects* ; Membrane Proteins/genetics* ; Animals ; Humans ; Nerve Tissue Proteins/genetics* ; Tumor Suppressor Protein p53/genetics* ; Male ; Mice

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

Objective To investigate the efficacy and safety of endoscopic radiofrequency ablation on patients with advanced stage unresectable cholangiocarcinoma. Methods Clinical data of 45 cases with unresectable cholangiocarcinoma who underwent endoscopic retrograde cholangiopancreatography from October 2011 to October 2014 were collected. The patients were divided into two groups: the group A included 23 cases undergoing radiofrequency ablation, and the group B included 22 cases without ablation. The occurrence of complications, the postoperative levels of CA19-9 and total bilirubin ( TBIL) in blood plasma, the patency of stents, and survival period were compared between the two groups. Results All of the 45 patients completed treatment, and no perforation, bleeding and bile leakage occurred. In the group A, 2 patients got fever and 5 patients got pancreatitis after operation, and the number in the group B was 3 and 4, respectively. Their symptoms disappeared after suitable treatment. The postoperative pain rate in group A ( 21. 7％, 5/23) was significantly lower than that of group B ( 54. 5％, 12/22,χ2=5. 148, P=0. 023) . At 7th day of post-operation, the levels of CA19-9 in the two groups were 960. 5 ± 362. 7 U/mL and 979. 3 ± 378. 1 U/mL, respectively, and the levels of TBIL were 95. 25±28. 36μmol/L and 98. 75±20. 76μmol/L, respectively, which were not significantly different between the two groups( P>0. 05) , but were significantly decreased compared with the levels of pre-operation ( P<0. 05) . The patency of self-expandable metal stent in group A ( 60. 0％, 6/10) was significantly higher than that of group B ( 10. 0％, 1/10,χ2=5. 495, P=0. 019) 9 months after operation. Kaplan-Meier analysis showed that the median survival time in the two groups had no statistical difference [ 271. 0 days ( 95％CI: 168. 4-373. 4days ) VS 245. 0 days ( 95％CI:200. 3-289. 7 days), χ2=1. 380, P=0. 258]. Conclusion For the patients with advanced unresectable cholangiocarcinoma, endoscopic radiofrequency ablation is able to relieve cancer pain, prolong the patency of stents, and improve the life quality, which deserves clinical applications.

Objective To compare the efficacy of percutaneous radiofrequency ablation (PRFA) and repeat hepatectomy for solitary recurrent hepatocellular carcinoma (HCC) with the diameter≤3 cm. Methods The clinical data of 151 patients with recurrent HCC (diameter≤3 cm) who were admitted to the Cancer Center of Sun Yat-Sen University from January 1999 to December 2009 were retrospectively analyzed. Of all the patients, 79received PRFA (PRFA group) and 72 received repeat hepatectomy (repeat hepatectomy group). The survival rate, morbidity and recurrence of the tumor between the two groups were compared. All data were analyzed using t test, chi-square test or Log-rank test, and the survival of the patients were analyzed using the Kaplan-Meier method. Results The mobidities of the PRFA group and repeat hepatectomy group were 13% (10/79) and 36%(26/72), respectively, with a significant difference between the two groups (x2=11.411, P＜0.05). The cumulative 1-, 2-, 3-, 4-, 5-year survival rates were 89.7%, 75.2%, 67.1%, 61.5%, 56.6% in the PRFA group, and 86.0%, 67.6%, 53.6%, 44.1%, 40.2% in the repeat hepatectomy group, with no significant difference between the two groups (x2=1.610, P＞0.05). The cumulative 4-, 5-year survival rates of the PRFA group were significant higher than those in the repeat hepatectomy group (x2=4.682, 4. 196, P ＜ 0.05). The local tumor recurrence rate of the PRFA group was 5% (4/79), and the incisal margin recurrence rate was 3% (2/72) in the repeat hepatectomy group, with no significant difference between the two groups (x2=0.565, P＞0.05). Conclusion As a less invasive treatment method, PRFA is superior to repeat hepatectomy for solitary recurrent HCC with the diameter≤3 cm.

Objective This retrospective study was to explore the efficacy and determine the risk factors of survival for recurrent hepatocellular carcinoma ( HCC) treated by repeat hepatectomy. Methods From January 1995 till December 2010, 60 patients with recurrent HCCs, were treated by repeat hepatectomy.The significance of seventeen clinical or pathological variables in the risk factors of overall survival were assessed. Results The overall survival 1,3, and 5-year survival rates were 76. 3% , 40.7% and 25. 0% (from repeat hepatectomy), and 95. 0% , 62. 6% and 43. 3% ( from initial hepatectomy) , respectively.Univariate analysis indicated that tumor size at initial hepatectomy, recurrence interval from initial hepatectomy, serum albumin(ALB) level, resection margin, diameter of largest recurrence tumor and rumor vascular invasion were significant prognostic factors(P <0. 05, Kaplan-Meier Log-rank test). Multivariate analysis showed recurrence interval from initial hepatectomy, resection margin, diameter of largest recurrence tumor and rumor vascular invasion were significant prognostic factors(P<0.05, Cox proportional hazards model).Conclusion Repeat hepatectomy is effective for recurrent HCC. Recurrence interval from initial hepatectomy, resection margin, diameter of largest recurrence tumor and rumor vascular invasion were significant prognostic factors.