MFSD5 identified as a receptor mediating lipoprotein(a) uptake and calcification in heart valve cells, with variants linked to aortic stenosis (Circulation 2024)

Original title: Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease

Circulation · 8 November 2023 · 8

Rogers MA, Bartoli-Leonard F, Zheng KH, Small AM, Chen HY, Clift CL, Asano T, Kuraoka S, Blaser MC, Perez KA, Natarajan P, Yeang C et al.

Using unbiased ligand-receptor capture mass spectrometry, the authors identified MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor or cofactor for Lp(a) uptake into valvular cells. Reducing MFSD5 expression, via a computationally identified small molecule or small interfering RNA, suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. A meta-analysis found MFSD5 variants associated with aortic stenosis (P=0.027 after correction for multiple hypothesis testing), with evidence suggesting an interaction with plasma Lp(a) levels. The findings identify MFSD5 as a candidate drug target for calcific aortic valve disease, for which no pharmacological therapy currently exists.

Original abstract

Background: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake.

Methods: Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake.

Results: Reducing MFSD5 expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. MFSD5 variants were associated with aortic stenosis (P=0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels.

Conclusions: MFSD5 knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of MFSD5 variants associating with aortic stenosis, supports further preclinical assessment of MFSD5 in cardiovascular diseases, the leading cause of death worldwide.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.