In general, calcification is a common physiological procedure to form bones and cartilage but when this calcification occurs in soft tissues, i.e., is known as an ectopic calcification. Calcific nodules and osteochondrogenic differentiations are the characteristics and of course, it is a pathophysiological condition. It is so far reported in several tissues namely the Kidney, heart, skin, eyes `and brain. In our two different papers, we worked on two different model organs. Statistics showed CAVD affects 13% of the total population above the age of 65. Calcification in the soft aortic valve is known as CAVD. In the picture, we can see the difference between a normal aortic valve and a calcific aortic valve in an open and closed condition. Two major cell populations were found in aortic valves. 1) VICs – valve interstitial cells and 2) VECs- valve endothelial cells. Previous research showed that VICs are more prone to calcify than VECs, so we chose VICs as our research interest. A calcified plaque on the surface of a senile cataractous lens (CL) isolated from a 79-year-old male patient was identified and its chemical composition was quantified using Fourier transform infrared (FTIR) and confocal Raman micro spectroscopies. No previously described mechanism could properly characterize the presence of HA in lens cataracts. Calcification was reported in other areas of the eyes as well like eyelids, sclera, cornea, lens, and retina. The inner structure of the lens consists of lens epithelium cells a cuboidal monolayer. As previous research showed that VICs and HuLECs both can go through the osteogenic transdifferentiation under the stimulation of high phosphate, we tried to see if a strong antioxidant system like the NRF2/HO-1 axis can revert or delay the procedure. NRF2 is a key regulator of the antioxidant system. In normal conditions, it goes through proteasomal degradation by the keap1/cul3 complex in the cytosol. Under stress conditions, it goes to the nucleus binds to the ARE (Anti-oxidant response element), and activates its downstream regulators like HO-1 (Heme oxygenase 1). HO-1 is an enzyme able to deplete heme into equimolar bilirubin through biliverdin, CO, and iron through ferritin. Heme plays a very contrasting role in our physiological system. Free heme can produce lots of ROS on the other hand heme degradation products like iron and bilirubin have anti-oxidant properties as well. So, to understand the bigger and complex picture we used heme as an inducer of the NRF2/HO-1 axis. We found that heme-mediated activation of the Nrf2/HO-1 axis can protect against high phosphate-induced calcification of valve interstitial cells and lens epithelial cells. We also discovered that inhibition of Nrf2 and HO-1 activities altered the protective effect of heme towards the high phosphate-induced calcification of valve interstitial cells and lens epithelial cells. Since iron is indeed the most important among the degradation products of heme in lens calcification, the effect of bilirubin, CO, and iron on valvular interstitial cells is more variegated. The generation of reactive oxygen species (ROS) by heme is important to activate the Nrf2/HO-1 axis in high phosphate-induced calcification of lens epithelial cells. This research, I feel, can contribute to a better understanding of the relationship between CKD, cataracts, and CAVD. Although we show here a beneficial effect of heme against VIC and HuLEC calcification, before we administer heme to patients to prevent calcification (as a form of heme arginate, a drug in use to treat acute porphyrias), we should consider the well-known pro-oxidant and pro-inflammatory nature of heme. We showed here that the beneficial effect of heme relies on the activation of the Nrf2 antioxidant system. Therefore, using other dietary Nrf2 inducers such as curcumin, resveratrol, or sulforaphane could be a safer approach.