Suppose $a,b,c,d\in R$ are powers of prime elements satisfying $ab=cd$. Let us write $a\sim_R c$ when $a,c$ are associates in $R$. Failure of $R$ to be a UFD means $$\neg (a\sim c\;\vee\;a\sim d).$$
A possible cause for this is that the disjunction holds locally but not globally. In other words, there may be some open cover $(U_i)_{i\in I}$ of $\operatorname{Spec}R$ such that $$\forall i\in I\;(a\sim_{U_i} c\;\vee\;a\sim_{U_i} d),$$ but such that exist $i\neq j$ such that only $a\sim_{U_i} c$ while only $a\sim_{U_j} d$.
(This already hints at some involvement of (co)homology as an obstruction to globalizing.)
Let us suppose indeed that only $a\sim_{U_i} c$ and only $a\sim_{U_j} d$. By further localizing each case, say at $c,d$ respectively, the associate condition becomes
$$a|_{D_c}\in R_c^\times, \; a|_{D_d}\in R_d^\times. $$
Thus $a\in R$ is invertible on each of the principal opens $D_c,D_d$, and yet it is not invertible on their union. This means the shape of the scheme $(\operatorname{Spec}R,R)$ is in some sense complicated.
This seems related to homology, although the $a\in R$ is a global function. What doesn't globalize is local invertibility. I don't see a naive connection to line bundles yet either.
In the example of the circle $R=\frac{\mathbb R[x,y]}{ \left\langle x ^2+y^2-1 \right\rangle }$, we have the open cover $D_{1-y},D_{1+y}$ by two arcs-minus-a-point. On each of them, the regular function $x\in R$ is invertible: on $D_{1-y}$ we have that $\frac{x}{1-y}$ is a unit and on $D_{1+y}$ we have that $\frac{x}{1+y}$ is a unit. However, $x\notin R^\times$. Indeed every coset in $R$ has a unique representative of the form $f_1+yf_2$ for $f_1,f_2\in \mathbb R[x]$ and such representatives can be used to calculate $R^\times$ and infer $x\notin R^\times $ (I think).