Objective To explore the safeguarding effect of trifluoperazine (TFP) when amalgamated with cyclophosphamide (CTX) on arresting the mesangial cell cycle at the G0/G1 phase in lupus nephritis (LN)-afflicted mice. Methods Six C57BL/6 mice were used as the control group (N), and 24 MRL/LPR mice of the same week were randomly divided into LN, LN+TFP, LN+CTX, and LN+1/2TFP+1/2CTX. Mice in the LN+TFP were given 30 mg/kg of TFP per day. In the LN+CTX group, mice were injected with 60mg/kg of CTX intraperitoneally once a week, while in the LN+1/2TFP+1/2CTX group, mice were given 15mg/kg of TFP orally every day and injected with 60mg/kg of CTX intraperitoneally every two weeks. After 12 weeks of treatment, the experiment was completed and specimens were obtained. HE staining and PAS staining were used to the morphological detection of kidneys. The biochemical spectrophotometry were used to the liver and kidney function indicators of each group of mice. WB method was used to the expression of PCNA and Ki67 protein. Glomerular mesangial cells were divided into N, 20%FBS, 20%FBS+TFP, 20%FBS+CTX, 20% FBS+1/2TFP+1/2CTX. Flow cytometry was used to detect the cell cycle of mesangial cells in each group, and the proliferation of mesangial cells in each group was detected by diphenyltetrazolium bromide salt (MTT) method. WB was used to the expressions of AKT, CyclinD1 and p21 in mesangial cells. Results The in vivo experiment results show that the pathological damage to mesangial cells, BUN and SCR levels were all lower in the CTX+TFP group than in the LN group (P<0.05), and also lower than in the LN+CTX group and the LN+TFP group treated with single drugs (p<0.05). The expression of PCNA and Ki67 protein in kidney tissue of mice in the LN 1/2TFP 1/2CTX group was lower than that in the LN group and lower than that in the LN CTX group and LN TFP group (F Ki67=36.08, F PCNA=10.04, P<0.01). In vitro experiments The MTT experiments conducted in vitro revealed striking disparities in the combined effects of different groups over time (F group=337.83, F time=55.96, F interaction=7.73, P<0.001). Furthermore, flow cytometry analysis demonstrated a notable increase in the percentage of cells in the G0/G1 phase within the 20% FBS 1/2CTX 1/2TFP group, accompanied by a significant decrease in cells in the S and G2 phases when compared to treatment with the drug alone. The WB results showed that the expression of p21 protein in the 20% FBS 1/2CTX 1/2TFP group was higher than that in the 20% FBS group and higher than that in the 20% FBS CTX group and the 20% FBS TFP group with single medication (F p21=12.78, P<0.01), in the group with 20% FBS+1/2 CTX+1/2 TFP, the expression of CyclinD1 and p-AKT/AKT protein was lower than the group with 20% FBS and lower than the groups with 20% FBS+CTX and 20% FBS+TFP taken alone(F p-AKT/AKT=32.88, F CyclinD1=13.59, P<0.01).Conclusion The reduction of cyclophosphamide combined with trifluoperazine can arrest the mesangial cell cycle at the G0/G1 phase, so as to inhibit the proliferation of mesangial cells, thereby protecting lupus nephritis mice