Complementary metal oxide semiconductor (CMOS) image sensors have become increasingly widely used in the field of radiation environments due to their numerous advantages, and their radiation effects have also attracted much attention. Some experimental studies have shown a decrease in the saturation output of CMOS image sensors after irradiation, while others have reported an increase. This article conducts further in-depth research on the inconsistent result based on proton irradiation experiments and TCAD simulations, analyzing the degradation mechanism in full well capacity (FWC), conversion factor (CVF), and saturation output of the 4T pinned photodiode (PPD) CMOS image sensors due to proton cumulative radiation effects. In experiments, the sensors are irradiated by 12 MeV and 60 MeV protons with a fluence up to 2×10¹² p/cm². The sensors are unbiased during irradiation. The experimental results show that proton irradiation at 12 MeV and 60 MeV results in an increase of 8.2% and 7.3% in conversion gain, respectively, and a decrease of 7.3% and 3.8% in full well capacity, respectively. The saturation output shows no significant change trend under 12 MeV proton irradiation, but increases by 3% under 60 MeV proton irradiation. In TCAD simulation, a three-dimensional 4T PPD pixel model is constructed. A simulation method that combines the Traps and Gamma Radiation model within TCAD and minority carrier lifetime mathematical model is employed to conduct global and local cumulative proton irradiation simulations for analyzing degradation mechanisms. It is proposed that the degradation of saturation output at the pixel level is determined by the FWC of PPD, the physical characteristics of the reset transistor and the capacitance of floating diffusion, but they have opposite effects. Proton irradiation leads to the accumulation of oxide-trapped positive charges in the shallow trench isolation on both sides of PPD, resulting in the formation of leakage current path in silicon, thereby reducing the full well capacity. A decrease in FWC leads to a decrease in saturation output. While, the radiation effect of the reset transistor causes the FD potential to increase during the FD reset phase, further leading to an increase in saturation output. Irradiation causes a decrease in the capacitance of the floating diffusion, resulting in an increase in conversion factor and consequently increasing the saturation output. The difference in radiation sensitivity among the three influence factors at the pixel level may result in a decrease or increase in saturation output with proton fluence. The above work comprehensively reveals and analyzes the mechanism of degradation in FWC, CVF and saturation output after irradiation, and the research results have certain guiding significance for the radiation damage analysis of CMOS image sensors.